AU2024205205A1

AU2024205205A1 - Methods for treating SARS CoV-2 infections

Info

Publication number: AU2024205205A1
Application number: AU2024205205A
Authority: AU
Inventors: Tomas Cihlar; Anuoluwapo OSINUSI; Danielle L. PORTER
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 2020-01-27
Filing date: 2024-07-30
Publication date: 2024-08-15
Also published as: US20210283150A1; US20230346812A1; CN114641299A; CA3163424A1; TW202140046A; CN118766947A; EP4096678A1; CN118662520A; WO2021154687A1; US11660307B2; TW202313067A; JP2023512656A; KR20220132608A; AU2021214911A1; TWI789695B

Abstract

OF THE DISCLOSURE Provided are methods for treating 2019-nCoV virus (SARS-CoV-2) infections by administering nucleosides and prodrugs thereof, of Formula I: R8 RIO R 7 N N R9 R 4 R1 w3 Ri2 wherein the l' position of the nucleoside sugar is substituted.

Description

METHODS FOR TREATING SARS COV-2 INFECTIONS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This Application is a divisional of Australian patent application 2021214911 and

claims the benefit of U.S. Provisional Application 63/031,373 filed on May 28, 2020, U.S.

Provisional Application 62/985,194 filed on March 4, 2020, U.S. Provisional Application

62/976,671 filed on February 14, 2020 and U.S. Provisional Application 62/966,440 filed on

January 27, 2020. The entire contents of all of these applications are incorporated herein by

reference in their entirety.

FIELD OF THE INVENTION

[0002] The invention relates generally to methods and compounds for treating or preventing

2019 novel coronavirus (2019-nCoV; SARS-CoV-2) infections (COVID-19), particularly

methods and nucleosides and prodrugs thereof for treating or preventing 2019-nCoV infections

(COVID-19).

BACKGROUND OF THE INVENTION

[0003] Coronaviruses, named for the crown-like spikes on their surfaces, infect mostly bats,

pigs and small mammals. They mutate easily and can jump from animals to humans, and from

one human to another. In recent years, they have become a growing player in infectious-disease

outbreaks world-wide. Recently, a novel coronavirus has been identified in the City of Wuhan,

China (Wuhan coronavirus; 2019-nCoV; SARS-CoV-2; may also be referred as transmissible

acute respiratory syndrome (TARS-CoV), clustered acute respiratory syndrome

coronavirus (CARS-CoV), or rapid spread respiratory syndrome coronavirus (RARS

CoV)). Currently, an outbreak of 2019-nCoV associated pneumonia is taking place in China.

There remains an urgent need to develop a safe and effective product to protect and/or treat

2019-nCoV infection.

SUMMARY OF THE INVENTION

[0004] Provided are methods and compounds for the treatment or prevention of infections

caused by the 2019-nCoV (COVID-19).

[0005] Provided is a method for treating or preventing a 2019-nCoV infection in a human in

need thereof comprising administering a therapeutically effective amount of a compound of

Formula I:

R8

R10

R7 N

0 N N

R0 R9 R4 R1

~3 R2

Formula I

or a pharmaceutically acceptable salt or ester, thereof;

wherein:

each R 1 is H or halogen;

each R 2 , R 3 , R 4 or R5 is independently H, ORa, N(Ra) 2 , N3, CN, N02, S(O),Ra, halogen,

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl or (C2-Cs)substituted alkynyl;

or any two R 2, R 3, R4 or R on adjacent carbon atoms when taken together are -O(CO)O- or

when taken together with the ring carbon atoms to which they are attached form a double bond;

R 6 is ORa, N(Ra) 2 , N3, CN, N02, S(O),Ra, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 ,

-C(=O)SR", -S(O)R", -S(O) 2 R", -S(O)(OR11 ), -S(O) 2 (OR"), -S0 2 NR"R 12 , halogen,

(Ci-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl, (C2-Cs)substituted alkynyl, or

(C6-C20)aryl(C1-Cs)alkyl;

R 7 is selected from a group consisting of

a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R",

-S(O) 2R",-S(O)(OR"l),-S(O) 2(OR"),or-SO 2NR"R1 2

, wherein each (C1-C)alkyl, (C2-C)alkenyl, (C2-Cs)alkynyl or

(C6-C20)aryl(Cl-C)alkyl of each R" or R 12 is, independently,

optionally substituted with one or more halo, hydroxy, CN, N3,

N(Ra) 2 or ORa; and wherein one or more of the non-terminal

carbon atoms of each said (C1-C)alkyl may be optionally

replaced with -0-, -S- or -NRa_

b)

0 0 00 0o HO-- / 0- /

HO HO HO or O

c)

Rc 0 Rc S Rl 0O-P Re 0 -- P0 R R Re Rd e2 N 'Rd (CH 2 )n (CH 2 )n

0 0 0 0 S / O / 0 R Rf ,or R9 R9

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl,

N N

and

Rd is H or CH 3 ;

R° and Re2 are each independently H, (Cl-C6)alkyl or benzyl;

Rf is selected from H, (C1-C8)alkyl, benzyl, (C3-C)cycloalkyl,

and -CH2-(C3-C6)cycloalkyl;

R9 is selected from (C1-C8)alkyl, -O-(C1-C8)alkyl, benzyl,

-O-benzyl, -CH2-(C3-C)cycloalkyl,

-O-CH2-(C3-C6)cycloalkyl, and CF 3 ; and

n' is selected from 1, 2, 3, and 4; and

d) a group of the formula:

Q

z2

wherein:

Q is 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR 2;

Z' and Z2 , when taken together, are -Q'(C(RY)2)3Q -

wherein

each Q 1 is independently 0, S, or NR; and

each R is independently H, F, Cl, Br, I, OH, R,-C(=Q 2)R,

-C(=Q2)OR, -C(=Q2)N(R)2, -N(R)2, -+N(R)3, -SR,

-S(O)R, -S(O) 2R, -S(O)(OR), -S(O) 2(OR),

-OC(=Q)R, -OC(=Q2)OR, -OC(=Q2)(N(R)2),

-SC(=Q2)R, -SC(=Q2)OR, -SC(=Q2)(N(R)2),

-N(R)C(=Q2)R, -N(R)C(=Q2)OR,

-N(R)C(=Q 2)N(R) 2 , -SO 2 NR 2 , -CN, -N3, -N02,

-OR, or Z 3 ; or when taken together, two R on the

same carbon atom form a carbocyclic ring of 3 to 7

carbon atoms;

each Q 2 is independently, 0, S, NR, 'N(O)(R), N(OR),

*N(O)(OR), or N-NR2; or

Z' and Z2 are each, independently, a group of the Formula Ia:

Q2

Rx Q 3 _p 3

Q3

M2

Formula Ia

wherein:

each Q 3 is independently a bond, 0, CR 2 , NR, 'N(O)(R),

N(OR), *N(O)(OR), N-NR 2 , S, S-S, S(O), or

S(0)2;

M2 is 0, 1 or 2;

each RX is independently R or the formula:

Q2 RY RY Q2 R~ RY

. Q3 ol Q3 Q3- M12c Mld Mia M1c wherein: each Mla, Mlc, and Mid is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Z 3 is Z 4 or Z5;

Z4 is R,-C(Q 2 )Ry, -C(Q 2 )Z5 , -SO 2 RY, or -S0 2Z5;

and

Z 5 is a carbocycle or a heterocycle wherein Z5 is

independently substituted with 0 to 3 R

groups;

R 8 is halogen, NR"R1 2 , N(R1 1 )OR 1 1, NR 1 1NR 1 1R 1 2, N3, NO, N02, CHO, CN,

-CH(=NR"), -CH=NNHR"1, -CH=N(OR"1), -CH(OR"1)2, -C(=0)NR"R12

-C(=S)NR"R 12 , -C(=O)OR 1 1, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-C)alkyl, -S(O).(C1-Cs)alkyl,

(C6-C20)aryl(C1-Cs)alkyl, OR" or SR";

each R 9 orR10 is independently H, halogen, NRR 1 2 1 1 )OR , N(R 1 1 ,NR1 1 NRR1 2 , N3,

NO, N02, CHO, CN, -CH(=NR"), -CH=NHNR", -CH=N(OR1 1 ), -CH(OR 1 ) 2 ,

-C(=O)NR"R 12 , -C(=S)NR"R 12 , -C(=O)OR 1 1, R1 1, OR" or SR";

each R 1 1 or R 12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-Cs)alkyl, -S(O)n(C1-Cs)alkyl or

(C6-C20)aryl(C-C)alkyl; or R 1 1and R 12 taken together with a nitrogen to which

they are both attached form a 3 to 7 membered heterocyclic ring wherein any one

carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S- or

-NRa_ each Ra is independently H, (C1-C)alkyl, (C2-C)alkenyl, (C2-C)alkynyl,

(C6-C20)aryl(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, -C(=O)R, -C(=O)OR,

-C(=O)NR 2 , -C(=O)SR, -S(O)R, -S(O) 2 R, -S(O)(OR), -S(O) 2 (OR), or -SO 2 NR 2 ;

wherein

each R is independently H, (C-Cs) alkyl, (C-Cs) substituted alkyl, (C2-C)alkenyl,

(C 2 -Cs) substituted alkenyl, (C 2 -Cs) alkynyl, (C 2 -Cs) substituted alkynyl,

(C6-C20)aryl, (C6-C20)substituted aryl, (C2-C20)heterocyclyl, (C2-C20)substituted

heterocyclyl, (C6-C20)aryl(C1-Cs)alkyl or substituted (C-C20)aryl(C1-C)alkyl;

each n is independently 0, 1, or 2; and

wherein each (C1-C)alkyl, (C2-C)alkenyl, (C2-C)alkynyl or (C-C20)aryl(C1-C)alkyl

of each R 2 , R 3 , R5 , R, R1 1 or R 12 is, independently, optionally substituted with

one or more halo, hydroxy, CN, N3, N(Ra) 2 or ORa; and wherein one or more of

the non-terminal carbon atoms of each said (C1-Cs)alkyl may be optionally

replaced with -0-, -S- or -NRa_

[0006] In another embodiment, the method comprises administering a therapeutically effective

amount of a racemate, enantiomer, diastereomer, tautomer, polymorph, pseudopolymorph,

amorphous form, hydrate or solvate of a compound of Formula I, or a pharmaceutically

acceptable salt or ester thereof, to a mammal in need thereof.

[0007] In some embodiments, provided is a method for treating or preventing a 2019-nCoV

infection (COVID-19) in a human in need thereof comprising administering a therapeutically

effective amount of a compound of Formula I:

R8

R1°

R7 N

00 0 N R9

R3 R2

Formula I

or a pharmaceutically acceptable salt thereof;

wherein:

each R 1 is H or halogen;

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl or (C2-Cs)substituted alkynyl;

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl, (C2-Cs)substituted alkynyl, or

(C6-C20)aryl(C1-Cs)alkyl;

R 7 is selected from a group consisting of: a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R",

-S(O) 2 R", -S(O)(OR"), -S(O) 2(OR"), or -S 12 2NR"R

, wherein each (Ci-C)alkyl, (C2-C)alkenyl, (C2-Cs)alkynyl or

(C6-C20)aryl(Cl-C)alkyl of each R" or R 12 is, independently,

optionally substituted with one or more halo, hydroxy, CN, N3,

N(Ra) 2 or ORa; and wherein one or more of the non-terminal

carbon atoms of each said (C1-C)alkyl may be optionally

replaced with -0-, -S- or -NRa_

b)

0 'O /OH O HO O

HO HO HO or HO HO HO

c)

Rc 0 Rc S 0O-P -- P0 Rl Re R N R Re Rd e2 'Rd (CH 2 )n (CH 2 )n

/ / 0 R Rf ,or Rg R9

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl,

N I N

and

Rd is H or CH 3 ;

R° and Re2 are each independently H, (C1-C6)alkyl or benzyl;

Q

Rf is selected from H, (C1-C8)alkyl, benzyl, (C3-C)cycloalkyl,

and -CH2-(C3-C6)cycloalkyl;

R9 is selected from (C1-C8)alkyl, -O-(C1-C8)alkyl, benzyl,

-O-benzyl, -CH2-(C 3-C)cycloalkyl,

-O-CH 2-(C 3-C 6)cycloalkyl, and CF 3 ; and

n' is selected from 1, 2, 3, and 4; and

d) a group of the formula:

Q

z2

wherein:

Q is 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR 2;

Z' and Z2 , when taken together, are -Q'(C(RY)2)3Q -

wherein

each Q 1 is independently 0, S, or NR; and

each R is independently H, F, Cl, Br, I, OH, R,-C(=Q 2)R,

-C(=Q2)OR, -C(=Q2)N(R)2, -N(R)2, -+N(R)3, -SR,

-S(O)R, -S(O) 2 R, -S(O)(OR), -S(O) 2 (OR),

-OC(=Q')R, -OC(=Q2)OR, -OC(=Q2)(N(R)2),

-SC(=Q2)R, -SC(=Q2)OR, -SC(=Q2)(N(R)2),

-N(R)C(=Q2)R, -N(R)C(=Q2)OR,

-N(R)C(=Q 2)N(R) 2 , -SO 2 NR 2 , -CN, -N3, -N02,

-OR, or Z 3 ; or when taken together, two R on the

same carbon atom form a carbocyclic ring of 3 to 7

carbon atoms;

1A each Q 2 is independently, 0, S, NR, 'N(O)(R), N(OR),

*N(O)(OR), or N-NR2; or

Z' and Z2 are each, independently, a group of the Formula Ia:

Q2

Rx Q 3 _p 3

Q3

M2

Formula Ia

wherein:

each Q 3 is independently a bond, 0, CR 2 , NR, 'N(O)(R),

N(OR), *N(O)(OR), N-NR 2 , S, S-S, S(O), or

S(0)2;

M2 is 0, 1 or 2;

each RX is independently R or the formula:

Q2 RY RY Q2

QQ3 3 Q3 Ry -M1L2c ' Mld Mia M1c

wherein:

each Mla, Mlc, and Md is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Z 3 is Z 4 or Z5

1 1

Z4 is R,-C(Q 2 )Ry, -C(Q 2)Z5 , -SO 2RY, or -S0 2Z5;

and

Z 5 is a carbocycle or a heterocycle wherein Z5 is

independently substituted with 0 to 3 R

groups;

R 8 is halogen, NR11 R1 2 , N(R1 1 )OR 1 1, NR 1 1NR 1 1R 1 2, N3, NO, N02, CHO, CN,

-CH(=NR"), -CH=NNHR"1, -CH=N(OR"1), -CH(OR"1)2, -C(=0)NR"R12

-C(=S)NR"R 12 , -C(=O)OR 1 1, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C 4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-C)alkyl, -S(O).(C1-Cs)alkyl,

(C6-C20)aryl(C1-Cs)alkyl, OR" or SR";

NO, N02, CHO, CN, -CH(=NR"), -CH=NHNR", -CH=N(OR1 1 ), -CH(OR 1 ) 2

, -C(=O)NR"R 12 , -C(=S)NR"R 12 , -C(=O)OR 1 1, R1 1, OR" or SR";

(C4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-Cs)alkyl, -S(O)n(C1-Cs)alkyl or

(C6-C20)aryl(C1-C)alkyl; or R 1 1and R 12 taken together with a nitrogen to which

they are both attached form a 3 to 7 membered heterocyclic ring wherein any one

-NRa_;

each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C6-C20)aryl(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, -C(=O)R, -C(=O)OR,

wherein each R is independently H, (C1 -Cs) alkyl, (C1 -Cs) substituted alkyl, (C2-C)alkenyl,

heterocyclyl, (C6-C20)aryl(Ci-Cs)alkyl or substituted (C-C20)aryl(C-Cs)alkyl;

each n is independently 0, 1, or 2; and

wherein each (C-Cs)alkyl, (C2-C)alkenyl, (C2-C)alkynyl or (C-C20)aryl(C-Cs)alkyl

one or more halo, hydroxy, CN, N3, N(Ra) 2 or ORa; and wherein one or more of

the non-terminal carbon atoms of each said (C-Cs)alkyl may be optionally

replaced with -0-, -S- or -NRa_

[0008] In another embodiment, the method comprises administering a therapeutically effective

acceptable salt thereof, to a mammal in need thereof. In a further embodiment, the method

comprises administering a therapeutically effective amount of a compound of Formula I, or a

pharmaceutically acceptable salt thereof, to a mammal in need thereof. In a further embodiment,

the method comprises administering remdesivir, or a pharmaceutically acceptable salt thereof, to

a mammal in need thereof. In another embodiment, the method comprises administering

remdesivir to a mammal in need thereof. In some embodiments, the mammal is a human.

[0009] In another embodiment, the method of treating or preventing a 2019-nCoV in a human

in need thereof comprises administering a therapeutically effective amount of a pharmaceutical

composition comprising an effective amount of a Formula I compound, or a pharmaceutically

acceptable salt or ester thereof, in combination with a pharmaceutically acceptable diluent or

carrier.

[0010] In another embodiment, the method of treating or preventing a 2019-nCoV infection in

a human in need thereof comprises administering a therapeutically effective amount of a

pharmaceutical composition comprising an effective amount of a Formula I compound, or a

pharmaceutically acceptable salt or ester thereof, in combination with at least one additional

therapeutic agent.

[0011] In another embodiment, the method comprises administering a therapeutically effective

amount of a combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of Formula I; or a

pharmaceutically acceptable salt, solvate, or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional

therapeutic agent active against the 2019-nCoV.

[0012] In another embodiment, the present application provides for a method of inhibiting a

2019-nCoV RNA-dependent RNA polymerase, comprising contacting a cell infected with the

2019-nCoV with an effective amount of a compound of Formula I, or a pharmaceutically

acceptable salts, solvate, and/or ester thereof.

[0013] In another embodiment, provided is the use of a compound of Formula I, or a

pharmaceutically acceptable salt, solvate, and/or ester thereof, to treat a viral infection caused by

the 2019-nCoV.

[0014] In another embodiment method comprises event driven administration of a compound

of Formula I, or a pharmaceutically acceptable salt thereof, to the subject.

il

DETAILED DESCRIPTION OF THE INVENTION

1. DEFINITIONS

[0015] Unless stated otherwise, the following terms and phrases as used herein are intended to

have the following meanings:

[0016] When trade names are used herein, applicants intend to independently include the trade

name product and the active pharmaceutical ingredient(s) of the trade name product.

[0017] As used herein, "a compound of the invention" or "a compound of Formula I" means a

compound of Formula I or a pharmaceutically acceptable salt, thereof. Similarly, with respect to

isolatable intermediates, the phrase "a compound of Formula (number)" means a compound of

that formula and pharmaceutically acceptable salts, thereof.

[0018] "Alkyl" is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms.

For example, an alkyl group can have 1 to 20 carbon atoms (i.e, C1-C20 alkyl), 1 to 8 carbon

atoms (i.e., C1-Cs alkyl), or 1 to 6 carbon atoms (i.e., C1-C alkyl). Examples of suitable alkyl

groups include, but are not limited to, methyl (Me, -CH 3), ethyl (Et, -CH2CH 3), 1-propyl (n-Pr,

n-propyl, -CH 2 CH 2 CH3), 2-propyl (i-Pr, i-propyl, -CH(CH 3) 2), 1-butyl (n-Bu, n-butyl,

-CH 2 CH 2 CH 2 CH3), 2-methyl-1-propyl (-Bu, i-butyl, -CH 2CH(CH 3) 2), 2-butyl (s-Bu, s-butyl,

-CH(CH 3)CH2CH 3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH 3 ) 3 ), 1-pentyl (n-pentyl,

-CH 2 CH 2 CH2 CH2 CH3), 2-pentyl (-CH(CH 3)CH 2CH2CH 3), 3-pentyl (-CH(CH 2CH 3)2),

2-methyl-2-butyl (-C(CH 3) 2CH 2CH3 ), 3-methyl-2-butyl (-CH(CH 3)CH(CH 3) 2),

3-methyl-i-butyl (-CH 2CH 2CH(CH 3) 2),2-methyl--butyl (-CH 2CH(CH 3)CH 2CH3 ),

1-hexyl (-CH 2CH2CH 2CH 2CH2CH 3), 2-hexyl (-CH(CH 3)CH 2CH2CH 2CH 3),

3-hexyl (-CH(CH 2CH 3)(CH 2CH2CH 3)), 2-methyl-2-pentyl (-C(CH 3) 2CH2 CH2CH 3),

3-methyl-2-pentyl (-CH(CH 3)CH(CH 3 )CH2CH 3),4-methyl-2-penty (-CH(CH 3)CH 2CH(CH 3) 2 ),

1 i

3-methyl-3-pentyl (-C(CH 3 )(CH 2CH 3) 2),2-methyl-3-pentyl (-CH(CH 2CH 3)CH(CH 3 )2 ),

2,3-dimethyl-2-butyl (-C(CH 3) 2CH(CH 3) 2), 3,3-dimethyl-2-butyl (-CH(CH 3 )C(CH3) 3 , and octyl

(-(CH 2) 7CH 3).

[0019] "Alkoxy" means a group having the formula -0-alkyl, in which an alkyl group, as

defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an

alkoxy group can have 1 to 20 carbon atoms (i.e., C1-C20 alkoxy), 1 to 12 carbon atoms(i.e.,

C1-C 12 alkoxy), or 1 to 6 carbon atoms(i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups

include, but are not limited to, methoxy (-O-CH 3 or -OMe), ethoxy (-OCH 2CH 3 or -OEt),

t-butoxy (-O-C(CH 3) 3 or -OtBu) and the like.

[0020] "Haloalkyl" is an alkyl group, as defined above, in which one or more hydrogen atoms

of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can

have 1 to 20 carbon atoms (i.e., C1-C2 haloalkyl), 1 to 12 carbon atoms(i.e., C1-C 12 haloalkyl),

or 1 to 6 carbon atoms(i.e., C1-C alkyl). Examples of suitable haloalkyl groups include, but are

not limited to, -CF 3, -CHF 2 , -CFH 2 , -CH 2CF 3, and the like.

[0021] "Alkenyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon

atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp2 double bond. For example,

an alkenyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 8 carbon atoms (i.e.,

C2-Cs alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups

include, but are not limited to, ethylene or vinyl (-CH=CH 2), allyl (-CH 2 CH=CH2 ),

cyclopentenyl (-C5 H 7 ), and 5-hexenyl (-CH 2CH 2CH 2CH2CH=CH 2 ).

[0022] "Alkynyl" is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon

atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an

alkynyl group can have 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 8 carbon atoms (i.e.,

C2-Cs alkyne,), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl

groups include, but are not limited to, acetylenic (-C-CH), propargyl (-CH 2C=CH), and the like.

[0023] "Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon

radical having two monovalent radical centers derived by the removal of two hydrogen atoms

from the same or two different carbon atoms of a parent alkane. For example, an alkylene group

can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene

radicals include, but are not limited to, methylene (-CH 2 -), 1,1-ethyl (-CH(CH 3)-), 1,2-ethyl

(-CH 2CH 2-), 1,1-propyl (-CH(CH 2CH 3)-), 1,2-propyl (-CH 2CH(CH 3 )-), 1,3-propyl

(-CH 2CH 2CH2 -), 1,4-butyl (-CH 2CH2CH 2CH 2-), and the like.

[0024] "Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon

from the same or two different carbon atoms of a parent alkene. For example, and alkenylene

group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical

alkenylene radicals include, but are not limited to, 1,2-ethylene (-CH=CH-).

[0025] "Alkynylene" refers to an unsaturated, branched or straight chain or cyclic

hydrocarbon radical having two monovalent radical centers derived by the removal of two

hydrogen atoms from the same or two different carbon atoms of a parent alkyne. For example,

an alkynylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon

atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C-C-), propargyl

(-CH 2 C-C-), and 4-pentynyl (-CH 2CH2CH 2C=C-).

[0026] "Amino" refers generally to a nitrogen radical which can be considered a derivative of

ammonia, having the formula -N(X) 2 , where each "X" is independently H, substituted or

unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted

1'7 heterocyclyl, etc. The hybridization of the nitrogen is approximately sp 3 . Nonlimiting types of amino include -NH 2, -N(alkyl)2, -NH(alkyl), -N(carbocyclyl)2, -NH(carbocyclyl),

-N(heterocyclyl)2, -NH(heterocyclyl), -N(aryl)2, -NH(aryl), -N(alkyl)(aryl),

-N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), -N(aryl)(heteroaryl),

-N(alkyl)(heteroaryl), etc. The term "alkylamino" refers to an amino group substituted with at

least one alkyl group. Nonlimiting examples of amino groups include -NH 2, -NH(CH 3),

-N(CH 3) 2, -NH(CH 2CH3 ), - N(CH 2CH3 )2 , -NH(phenyl), -N(phenyl)2, -NH(benzyl), -N(benzyl)2,

etc. Substituted alkylamino refers generally to alkylamino groups, as defined above, in which at

least one substituted alkyl, as defined herein, is attached to the amino nitrogen atom.

Non-limiting examples of substituted alkylamino includes -NH(alkylene-C(O)-OH),

-NH(alkylene-C(O)-O-alkyl), -N(alkylene-C(O)-OH)2, -N(alkylene-C(O)-O-alkyl)2, etc.

[0027] "Aryl" means an aromatic hydrocarbon radical derived by the removal of one hydrogen

atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group

can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl

groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted

benzene, naphthalene, anthracene, biphenyl, and the like.

[0028] "Arylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen atoms

bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with an aryl

radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl,

naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like.

The arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon

atoms and the aryl moiety is 6 to 14 carbon atoms.

[0029] "Arylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms

bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp2 carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the aryl groups disclosed herein, and the alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein. The arylalkenyl group can comprise 8 to carbon atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

[0030] "Arylalkynyl" refers to an acyclic alkynyl radical in which one of the hydrogen atoms

bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp carbon atom, is

replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any

of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for

example, any of the alkynyl groups disclosed herein. The arylalkynyl group can comprise 8 to

carbon atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14

carbon atoms.

[0031] The term "substituted" in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy,

heterocyclyl, heteroaryl, carbocyclyl, etc. , for example, "substituted alkyl", "substituted

alkylene", "substituted aryl", "substituted arylalkyl", "substituted heterocyclyl", and

"substituted carbocyclyl" means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl

respectively, in which one or more hydrogen atoms are each independently replaced with a non

hydrogen substituent. Typical substituents include, but are not limited to, -X, RO-, =0,

-OR', -SRb, -S-, -NRb2 , -N+Rb3 , =NRb, -CX 3 , -CN, -OCN, -SCN, -N=C=, -NCS, -NO, -N02,

=N2, -N3, -NHC(=O)Rb, -OC(=)Rb, -NHC(=)NRb2, -S(=0) 2-, -S(=0) 20H, -S(=0) 2R ,

-OS(=0) 2ORb, -S(=0) 2NRb 2, -S(=O)Rb, -OP(=O)(ORb) 2 , -P(=O)(ORb) 2 , -P(=O)(O-) 2 ,

-P(=O)(OH) 2, -P(O)(ORb)(O-), -C(=)Rb, -C(=)X, -C(S)Rb, -C(O)ORb, -C(O)0-, -C(S)ORb,

-C(O)SRb, -C(S)SRb, -C(O)NRb2 , -C(S)NRb2 , -C(=NRb)NRb2 , where each X is independently a

halogen: F, Cl, Br, or I; and each R is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise indicated, when the term "substituted" is used in conjunction with groups such as arylalkyl, which have two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both. The term

"C1-Cs substituted alkyl" refers to an alkyl group having 1 to 8 carbons which is substituted as

defined herein. Likewise, the term "C2-Cssubstituted alkenyl" refers an alkenyl having 2 to 8

carbons, substituted as defined herein; and the term "C2-Cs substituted alkynyl" refers to an

alkynyl group having 1 to 8 carbons substituted as defined herein. Similarly, term

"(C-C20)substituted aryl" refers to an aryl having 6 to 20 carbons, substituted as defined herein;

and term (C2-C20)substituted heterocyclyl refers to an heterocyclyl having 2 to 20 carbons,

which is substituted as defined herein.

[0032] A "prodrug" is defined in the pharmaceutical field as a biologically inactive derivative

of a drug that upon administration to the human body is converted to the biologically active

parent drug according to some chemical or enzymatic pathway.

[0033] One skilled in the art will recognize that substituents and other moieties of the

compounds of Formula I-IV should be selected in order to provide a compound which is

sufficiently stable to provide a pharmaceutically useful compound which can be formulated into

an acceptably stable pharmaceutical composition. Compounds of Formula I-IV which have such

stability are contemplated as falling within the scope of the present invention.

[0034] "Heteroalkyl" refers to an alkyl group where one or more carbon atoms have been

replaced with a heteroatom, such as, 0, N, or S. For example, if the carbon atom of the alkyl

group which is attached to the parent molecule is replaced with a heteroatom (e.g., 0, N, or S)

the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH 3, etc.), an amine

(e.g., -NHCH 3, -N(CH 3) 2, etc.), or a thioalkyl group (e.g., -SCH 3 ). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molecule is replaced with a heteroatom (e.g., 0, N, or S) the resulting heteroalkyl groups are, respectively, an alkyl ether

(e.g., -CH2CH 2-0-CH 3 , etc.), an alkyl amine (e.g., -CH 2NHCH 3, -CH 2N(CH 3) 2, etc.), or a

thioalkyl ether (e.g.,-CH2-S-CH3). If a terminal carbon atom of the alkyl group is replaced with

a heteroatom (e.g., 0, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl

group (e.g., -CH2CH 2-OH), an aminoalkyl group (e.g., -CH2NH 2), or an alkyl thiol group (e.g.,

-CH 2CH 2-SH). A heteroalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon

atoms, or 1 to 6 carbon atoms. A C1-C heteroalkyl group means a heteroalkyl group having 1 to

6 carbon atoms.

[0035] "Heterocycle" or "heterocyclyl" as used herein includes by way of example and not

limitation those heterocycles described in Paquette, Leo A.; Principles of Modem Heterocyclic

Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The

Chemistry of Heterocyclic Compounds, A Series of Monographs" (John Wiley & Sons, New

York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc.

(1960) 82:5566. In one specific embodiment of the invention "heterocycle" includes a

"carbocycle" as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been

replaced with a heteroatom (e.g. 0, N, or S). The terms "heterocycle" or "heterocyclyl"

includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic

rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of

the substituents disclosed herein including carbonyl groups. A non-limiting example of a

carbonyl substituted heterocyclyl is:

N INH O

[0036] Examples of heterocycles include by way of example and not limitation pyridyl,

dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized

tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,

benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl,

piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,

tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,

azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl,

pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl,

isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H

quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,

4aH-carbazolyl, carbazolyl, 3-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl,

phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl,

imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,

quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl,

benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

OC

[0037] By way of example and not limitation, carbon bonded heterocycles are bonded at

position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6

of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,

tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an

oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole,

position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of

a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon

1) bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,

4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6

pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5

thiazolyl.

[0038] By way of example and not limitation, nitrogen bonded heterocycles are bonded at

position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole,

imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,

piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline,

position 4 of a morpholine, and position 9 of a carbazole, or -carboline. Still more typically,

nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,

1-pyrazolyl, and 1-piperidinyl.

[0039] "Heterocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen

atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, is replaced with a

heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety). Typical heterocyclyl alkyl groups

include, but are not limited to heterocyclyl-CH2-, 2-(heterocyclyl)ethan-1-yl, and the like,

wherein the "heterocyclyl" portion includes any of the heterocyclyl groups described above,

including those described in Principles of Modem Heterocyclic Chemistry. One skilled in the

art will also understand that the heterocyclyl group can be attached to the alkyl portion of the

heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the

proviso that the resulting group is chemically stable. The heterocyclyl alkyl group comprises 3

to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbon atoms and the

heterocyclyl moiety is 2 to 14 carbon atoms. Examples of heterocyclylalkyls include by way of

example and not limitation 5-membered sulfur, oxygen, and/or nitrogen containing heterocycles

such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

[0040] "Heterocyclylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen

atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also a sp2 carbon

atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene- moiety). The

heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups

described herein, including those described in Principles of Modem Heterocyclic Chemistry, and

the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups

disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be

attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or

a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The

heterocyclyl alkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the

heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon

atoms.

[0041] "Heterocyclylalkynyl" refers to an acyclic alkynyl radical in which one of the

hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp

carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkynylene- moiety).

The heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl

groups described herein, including those described in Principles of Modern Heterocyclic

Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl

groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group

can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon

bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable.

The heterocyclyl alkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the

heterocyclyl alkynyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon

atoms.

[0042] "Heteroaryl" refers to an aromatic heterocyclyl having at least one heteroatom in the

ring. Non-limiting examples of suitable heteroatoms which can be included in the aromatic ring

include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of

those aromatic rings listed in the definition of "heterocyclyl", including pyridinyl, pyrrolyl,

oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl,

carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl,

pyridazyl, pyrimidyl, pyrazyl, etc.

[0043] "Carbocycle" or "carbocyclyl" refers to a saturated (i.e., cycloalkyl), partially

unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon

atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a

polycycle. Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or 6 ring

atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5],

[5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro

fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl,

cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1

cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examples of

bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.

[0044] "Carbocyclylalkyl" refers to an acyclic alkyl radical in which one of the hydrogen

atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein.

Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl,

cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

9)51

[0045] "Arylheteroalkyl" refers to a heteroalkyl as defined herein, in which a hydrogen atom

(which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl

group as defined herein. The aryl groups may be bonded to a carbon atom of the heteroalkyl

group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl

group provides a chemically stable moiety. For example, an arylheteroalkyl group can have the

general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl,

-alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, any of

the alkylene moieties in the general formulae above can be further substituted with any of the

substituents defined or exemplified herein.

[0046] "Heteroarylalkyl" refers to an alkyl group, as defined herein, in which a hydrogen atom

has been replaced with a heteroaryl group as defined herein. Non-limiting examples of

heteroaryl alkyl include -CH2-pyridinyl, -CH2-pyrrolyl, -CH2-oxazolyl, -CH2-indolyl,

-CH2-isoindolyl, -CH2-purinyl, -CH2-furanyl, -CH2-thienyl, -CH2-benzofuranyl,

-CH2-benzothiophenyl, -CH2-carbazolyl, -CH2-imidazolyl, -CH2-thiazolyl, -CH2-isoxazolyl,

-CH2-pyrazolyl, -CH2-isothiazolyl, -CH2-quinolyl, -CH2-isoquinolyl, -CH2-pyridazyl,

-CH2-pyrimidyl, -CH2-pyrazyl, -CH(CH3)-pyridinyl, -CH(CH3)-pyrrolyl, -CH(CH3)-oxazolyl,

-CH(CH3)-indolyl, -CH(CH3)-isoindolyl, -CH(CH3)-purinyl, -CH(CH3)-furanyl,

-CH(CH3)-thienyl, -CH(CH3)-benzofuranyl, -CH(CH3)-benzothiophenyl, -CH(CH3)-carbazolyl,

-CH(CH3)-imidazolyl, -CH(CH3)-thiazolyl, -CH(CH3)-isoxazolyl, -CH(CH3)-pyrazolyl,

-CH(CH3)-isothiazolyl, -CH(CH3)-quinolyl, -CH(CH3)-isoquinolyl, -CH(CH3)-pyridazyl,

-CH(CH3)-pyrimidyl, -CH(CH3)-pyrazyl, etc.

[0047] The term "optionally substituted" in reference to a particular moiety of the compound

of Formula I-IV (e.g., an optionally substituted aryl group) refers to a moiety wherein all substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by substituents such as those listed under the definition of "substituted".

[0048] The term "optionally replaced" in reference to a particular moiety of the compound of

Formula I-IV (e.g., the carbon atoms of said (C1-Cs)alkyl may be optionally replaced by -0-, -S

, or -NRa-) means that one or more of the methylene groups of the (C1-C)alkyl may be replaced

by 0, 1, 2, or more of the groups specified (e.g., -0-, -S-, or -NRa_).

[0049] The term "non-terminal carbon atom(s)" in reference to an alkyl, alkenyl, alkynyl,

alkylene, alkenylene, or alkynylene moiety refers to the carbon atoms in the moiety that

intervene between the first carbon atom of the moiety and the last carbon atom in the moiety.

Therefore, by way of example and not limitation, in the alkyl moiety -CH 2(C*)H 2(C*)H 2CH 3 or

alkylene moiety -CH 2(C*)H 2 (C*)H 2CH 2- the C* atoms would be considered to be the non

terminal carbon atoms.

[0050] Certain Q and Q1 alternatives are nitrogen oxides such as *N(O)(R) or 'N(O)(OR).

These nitrogen oxides, as shown here attached to a carbon atom, can also be represented by

charge separated groups such as

0 O

R or OR,

respectively, and are intended to be equivalent to the aforementioned representations for the

purposes of describing this invention.

[0051] "Linker" or "link" means a chemical moiety comprising a covalent bond or a chain of

atoms. Linkers include repeating units of alkyloxy (e.g. polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.

[0052] The terms such as "oxygen-linked", "nitrogen-linked", "carbon-linked", "sulfur

linked", or "phosphorous-linked" mean that if a bond between two moieties can be formed by

using more than one type of atom in a moiety, then the bond formed between the moieties is

through the atom specified. For example, a nitrogen-linked amino acid would be bonded

through a nitrogen atom of the amino acid rather than through an oxygen or carbon atom of the

amino acid.

[0053] In some embodiments of the compounds of Formula I-IV, one or more of Z' or Z2 are

independently a radical of a nitrogen-linked naturally occurring a-amino acid ester. Examples

of naturally occurring amino acids include isoleucine, leucine, lysine, methionine,

phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, cysteine,

glutamic acid, glutamine, glycine, proline, selenocysteine, serine, tyrosine, arginine, histidine,

ornithine and taurine. The esters of these amino acids comprise any of those described for the

substituent R, particularly those in which R is optionally substituted (C1-C8)alkyl.

[0054] The term "purine" or "pyrimidine" base comprises, but is not limited to, adenine,

N 6-alkylpurines, N 6-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl),

N 6-benzylpurine, N 6-halopurine, N 6 -vinylpurine, N 6 -acetylenic purine, N6 -acyl purine,

N 6-hydroxyalkyl purine, N6 -allylaminopurine, N6 -thioallyl purine, N2 -alkylpurines,

N 2-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine,

including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including

-fluorouracil, C 5-alkylpyrimidines, C 5 -benzylpyrimidines, C 5-halopyrimidines,

C 5 -vinylpyrimidine, C 5-acetylenic pyrimidine, C 5-acyl pyrimidine, C5 -hydroxyalkyl purine,

C 5 -amidopyrimidine, C 5-cyanopyrimidine, C 5 -5-iodopyrimidine, C 6 -iodo-pyrimidine, C 5 -

Br-vinyl pyrimidine, C6 -Br-vinyl pyriniidine, C 5-nitropyrimidine, C 5 -amino-pyrimidine,

N 2-alkylpurines, N 2-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl,

imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are

not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. The

purine and pyrimidine bases of Formula I-III are linked to the ribose sugar, or analog thereof,

through a nitrogen atom of the base. Functional oxygen and nitrogen groups on the base can be

protected as necessary or desired. Suitable protecting groups are well known to those skilled in

the art, and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and

t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl,

methanesulfonyl, and p-toluenesulfonyl.

[0055] Unless otherwise specified, the carbon atoms of the compounds of Formula I-IV are

intended to have a valence of four. In some chemical structure representations where carbon

atoms do not have a sufficient number of variables attached to produce a valence of four, the

remaining carbon substituents needed to provide a valence of four should be assumed to be

hydrogen. For example,

R8

R7 N

O N R9

R4e R1

R3 R2

has the same meaning as

R8 H

R7 N H H H ?_ 0 0 N R9

R4 R1

R3 R2

[0056] "Protecting group" refers to a moiety of a compound that masks or alters the properties

of a functional group or the properties of the compound as a whole. The chemical substructure

of a protecting group varies widely. One function of a protecting group is to serve as an

intermediate in the synthesis of the parental drug substance. Chemical protecting groups and

strategies for protection/deprotection are well known in the art. See: "Protective Groups in

Organic Chemistry", Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991.

Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist

in the efficiency of desired chemical reactions, e.g. making and breaking chemical bonds in an

ordered and planned fashion. Protection of functional groups of a compound alters other

physical properties besides the reactivity of the protected functional group, such as the polarity,

lipophilicity (hydrophobicity), and other properties which can be measured by common

analytical tools. Chemically protected intermediates may themselves be biologically active or

inactive. "Hydroxy protecting groups" refers to those protecting groups useful for protecting

hydroxy groups (-OH).

[0057] Protected compounds may also exhibit altered, and in some cases, optimized properties

in vitro and in vivo, such as passage through cellular membranes and resistance to enzymatic

degradation or sequestration. In this role, protected compounds with intended therapeutic

effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although in general it is more desirable if the products are pharmacologically innocuous.

[0058] The term "chiral" refers to molecules which have the property of non

superimposability of the mirror image partner, while the term "achiral" refers to molecules

which are superimposable on their mirror image partner.

[0059] The term "stereoisomers" refers to compounds which have identical chemical

constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0060] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and

whose molecules are not mirror images of one another. Diastereomers have different physical

properties, e.g. melting points, boiling points, spectral properties, reactivities and biological

properties. For example, the compounds of Formula I-IV may have a chiral phosphorus atom

when R 7 is

Q

z2

and Z' and Z 2 are different. When at least one of either Z' or Z 2 also has a chiral center, for

example with Z' or Z 2 is a nitrogen-linked, chiral, naturally occurring c-amino acid ester, then

the compound of Formula I-IV will exists as diastereomers because there are two centers of

chirality in the molecule. All such diastereomers and their uses described herein are encompassed by the instant invention. Mixtures of diastereomers may be separate under high resolution analytical procedures such as electrophoresis, crystallization and/or chromatography.

Diastereomers may have different physical attributes such as, but not limited to, solubility,

chemical stabilities and crystallinity and may also have different biological properties such as,

but not limited to, enzymatic stability, absorption and metabolic stability.

[0061] "Enantiomers" refer to two stereoisomers of a compound which are

non-superimposable mirror images of one another.

[0062] The modifier "about" used in connection with a quantity is inclusive of the stated value

and has the meaning dictated by the context (e.g., includes the degree of error associated with

measurement of the particular quantity).

[0063] The term "treating", as used herein, unless otherwise indicated, means reversing,

alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term

applies, or one or more symptoms of such disorder or condition. The term "treatment", as used

herein, refers to the act of treating, as "treating" is defined immediately above.

[0064] The term "therapeutically effective amount", as used herein, is the amount of

compound of Formula I-IV present in a composition described herein that is needed to provide a

desired level of drug in the secretions and tissues of the airways and lungs, or alternatively, in

the bloodstream of a subject to be treated to give an anticipated physiological response or

desired biological effect when such a composition is administered by the chosen route of

administration. The precise amount will depend upon numerous factors, for example the

particular compound of Formula I-IV, the specific activity of the composition, the delivery

device employed, the physical characteristics of the composition, its intended use, as well as

patient considerations such as severity of the disease state, patient cooperation, etc., and can

readily be determined by one skilled in the art based upon the information provided herein.

2')

[0065] The term "normal saline" means a water solution containing 0.9% (w/v) NaCl.

[0066] The term "hypertonic saline" means a water solution containing greater than 0.9%

(w/v) NaCl. For example, 3% hypertonic saline would contain 3% (w/v) NaCl.

[0067] "Forming a reaction mixture" refers to the process of bringing into contact at least two

distinct species such that they mix together and can react. It should be appreciated, however, the

resulting reaction product can be produced directly from a reaction between the added reagents

or from an intermediate from one or more of the added reagents which can be produced in the

reaction mixture.

[0068] "Coupling agent" refers to an agent capable of coupling two disparate compounds.

Coupling agents can be catalytic or stoichiometric. For example, the coupling agents can be a

lithium based coupling agent or a magnesium based coupling agent such as a Grignard reagent.

Exemplary coupling agents include, but are not limited to, n-BuLi, MgC2, iPrMgCl, tBuMgCl,

PhMgC1 or combinations thereof.

[0069] "Silane" refers to a silicon containing group having the formula SiR 4 , where each R

group can be alkyl, alkenyl, cycloalkyl, phenyl, or other silicon containing groups. When the

silane is linked to another compound, the silane is referred to as a "silyl" and has the formula

-SiR 3 .

[0070] "Halo-silane" refers to a silane having at least one halogen group linked to the silicon

atom. Representative halo-silanes have the formula Halo-SiR3, where each R group can be

alkyl, alkenyl, cycloalkyl, phenyl, or other silicon containing groups. Specific halo-silanes

include Cl-Si(CH 3) 3, and Cl-Si(CH 3) 2CH 2CH2 Si(CH 3) 2-Cl.

[0071] "Non-nucleophilic base" refers to an electron donor, a Lewis base, such as nitrogen

bases including triethylamine, diisopropylethyl amine, N,N-diethylaniline, pyridine, 2,6-lutidine,

2,4,6-collidine, 4-dimethylaminopyridine, and quinuclidine.

[0072] "Leaving group" refers to groups that maintain the bonding electron pair during

heterolytic bond cleavage. For example, a leaving group is readily displaced during a

nucleophilic displacement reaction. Suitable leaving groups include, but are not limited to,

chloride, bromide, mesylate, tosylate, triflate, 4-nitrobenzenesulfonate,

4-chlorobenzenesulfonate, 4-nitrophenoxy, pentafluorophenoxy, etc. One of skill in the art will

recognize other leaving groups useful in the present invention.

[0073] "Deprotection agent" refers to any agent capable of removing a protecting group. The

deprotection agent will depend on the type of protecting group used. Representative

deprotection agents are known in the art and can be found in Protective Groups in Organic

Chemistry, Peter G. M. Wuts and Theodora W. Greene, 4th Ed., 2006.

[0074] "Pharmaceutically acceptable salts" are non-toxic salts of a free base form of a

compound that possess the desired pharmacological activity of the free base. In some

embodiments, these salts are derived from inorganic or organic acids or bases. For example, a

compound that contains a basic nitrogen may be prepared as a pharmaceutically acceptable salt

by contacting the compound with an inorganic or organic acid. Non-limiting examples of

pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,

phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,

pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates,

acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates,

succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,

benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates,

methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besylates,

xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates,

phenylpropionates, phenylbutyrates, citrates, lactates, T-hydroxybutyrates, glycolates, tartrates,

and mandelates. Lists of other suitable pharmaceutically acceptable salts are found in

III

Remington: The Science and Practice of Pharmacy, 21" Edition, Lippincott Wiliams and

Wilkins, Philadelphia, Pa., 2006.

[0075] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein

also include salts derived from an appropriate base, such as an alkali metal (for example,

sodium, potassium), an alkaline earth metal (for example, magnesium), ammonium and NX 4

' (wherein X is C1-C4 alkyl). Also included are base addition salts, such as sodium or potassium

salts.

[0076] Pharmaceutically acceptable esters of compounds of Formula I include esters of

hydroxy groups, for example in-vivo hydrolysable esters of hydroxy groups. Examples of in

vivo hydrolysable esters of hydroxyl groups include those provided by C 1-6 alkyl carboxylic

acids.

2. COMPOUNDS OF THE PRESENT INVENTION

[0077] Reference will now be made in detail to certain embodiments of the invention,

examples of which are illustrated in the accompanying description, structures and formulas.

While the invention will be described in conjunction with the enumerated embodiments, it will

be understood that they are not intended to limit the invention to those embodiments. On the

contrary, the invention is intended to cover all alternatives, modifications, and equivalents,

which may be included within the scope of the present invention.

[0078] Provided is a method for treating a 2019-nCoV infection in a human in need thereof

comprising administering a therapeutically effective amount of a compound of Formula I:

I25

R8

R10

R7 N

O0 R9

6 "R R4 R1

R3 R2

Formula I

or a pharmaceutically acceptable salt or ester, thereof;

wherein:

each R 1 is H or halogen;

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl or (C2-Cs)substituted alkynyl;

R 6 is ORa, N(Ra) 2, N3, CN, N02, S(O),Ra, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 ,

-C(=O)SR", -S(O)R", -S(O) 2R", -S(O)(OR1 1 ), -S(O) 2 (OR"), -S0 2NR"R 12 , halogen,

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl, (C2-Cs)substituted alkynyl, or

(C6-C20)aryl(C1-Cs)alkyl;

R 7 is selected from a group consisting of a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R",

-S(O) 2 R", -S(O)(OR"), -S(O) 2(OR"), or -S 12 2NR"R

, wherein each (Ci-C)alkyl, (C2-C)alkenyl, (C2-Cs)alkynyl or

(C6-C20)aryl(Cl-C)alkyl of each R" or R 12 is, independently,

optionally substituted with one or more halo, hydroxy, CN, N3,

N(Ra) 2 or ORa; and wherein one or more of the non-terminal

carbon atoms of each said (C1-C)alkyl may be optionally

replaced with -0-, -S- or -NRa_

b)

0 'O HO-P -- '0 | P N- ||1 / HO HO O HO HO HO HO or HO HO HO

c)

Rc 0 Rc S 0O-P -- P0 Rl Re R N R Re Rd e2 'Rd (CH 2 )n (CH 2 )n

/ / 0 R Rf ,or Rg R9

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl,

N I N

and

Rd is H or CH 3 ;

R° and Re2 are each independently H, (C1-C6)alkyl or benzyl;

Rf is selected from H, (C1-C8)alkyl, benzyl, (C3-C)cycloalkyl,

and -CH2-(C3-C6)cycloalkyl;

R9 is selected from (C1-C8)alkyl, -O-(C1-C8)alkyl, benzyl,

-O-benzyl, -CH2-(C 3-C)cycloalkyl,

-O-CH 2-(C 3-C 6)cycloalkyl, and CF 3 ; and

n' is selected from 1, 2, 3, and 4; and

d) a group of the formula:

Q

z2

wherein:

Q is 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR 2;

Z' and Z2 , when taken together, are -Q'(C(RY)2)3Q -

wherein

each Q 1 is independently 0, S, or NR; and

each R is independently H, F, Cl, Br, I, OH, R,-C(=Q 2)R,

-C(=Q2)OR, -C(=Q2)N(R)2, -N(R)2, -+N(R)3, -SR,

-S(O)R, -S(O) 2 R, -S(O)(OR), -S(O) 2 (OR),

-OC(=Q')R, -OC(=Q2)OR, -OC(=Q2)(N(R)2),

-SC(=Q2)R, -SC(=Q2)OR, -SC(=Q2)(N(R)2),

-N(R)C(=Q2)R, -N(R)C(=Q2)OR,

-N(R)C(=Q 2)N(R) 2 , -SO 2 NR 2 , -CN, -N3, -N02,

-OR, or Z 3 ; or when taken together, two R on the

same carbon atom form a carbocyclic ring of 3 to 7

carbon atoms; each Q 2 is independently, 0, S, NR, 'N(O)(R), N(OR),

*N(O)(OR), or N-NR2; or

Z' and Z2 are each, independently, a group of the Formula Ia:

Q2

Rx Q 3 _p 3

Q3

RX M2

Formula Ia

wherein:

each Q 3 is independently a bond, 0, CR 2 , NR, 'N(O)(R),

N(OR), *N(O)(OR), N-NR 2 , S, S-S, S(O), or

S(0)2;

M2 is 0, 1 or 2;

each RX is independently R or the formula:

Q2 RY RY Q2 RR ..... 1 Q3 ." Q3 k Q3--,R - M12c ' Mld Mia M1c

wherein:

each Mla, Mlc, and Md is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Z 3 is Z 4 or Z5;

Z4 is R,-C(Q 2 )Ry, -C(Q 2 )Z5 , -SO2RY, or -SO2Z5

and

Z 5 is a carbocycle or a heterocycle wherein Z5 is

independently substituted with 0 to 3 R

groups;

-CH(=NR"), -CH=NNHR"1, -CH=N(OR"1), -CH(OR"1)2, -C(=0)NR"R12

-C(=S)NR"R 12 , -C(=O)OR 1 1, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C 4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-C)alkyl, -S(O).(C1-Cs)alkyl,

(C6-C20)aryl(C1-Cs)alkyl, OR" or SR";

NO, N02, CHO, CN, -CH(=NR"), -CH=NHNR", -CH=N(OR1 1 ), -CH(OR 1 ) 2

, -C(=O)NR"R 12 , -C(=S)NR"R 12 , -C(=O)OR 1 1, R1 1, OR" or SR";

(C4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-Cs)alkyl, -S(O)n(C1-Cs)alkyl or

they are both attached form a 3 to 7 membered heterocyclic ring wherein any one

-NRa_;

each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C6-C20)aryl(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, -C(=O)R, -C(=O)OR,

wherein

an each R is independently H, (C-Cs) alkyl, (C-Cs) substituted alkyl, (C2-C)alkenyl,

heterocyclyl, (C6-C20)aryl(C1-Cs)alkyl or substituted (C-C20)aryl(C1-C)alkyl;

each n is independently 0, 1, or 2; and

one or more halo, hydroxy, CN, N3, N(Ra) 2 or ORa; and wherein one or more of

the non-terminal carbon atoms of each said (C1-Cs)alkyl may be optionally

replaced with -0-, -S- or -NRa_

[0079] In another embodiment, provided is a method of treating a 2019-nCoV infection in a

human in need thereof comprising administering a therapeutically effective amount of a

compound of Formula I represented by Formula II:

R8

R7 N

0N N R9

H R1 3 2 R R

Formula II

or a pharmaceutically acceptable salt or ester, thereof;

wherein

R 1, R 3 , R 5, R 7 , R 8 and R 9 are as defined above for Formula I;

each R 2 is ORa or halogen; and

A1

R 6 is ORa, N(Ra) 2 , N3, CN, S(O)Ra, -C(=O)R", -C(=O)OR " , -C(=O)NR"R 12 , -C(=O)SR",

S(O)R", -S(O) 2 R", -S(O)(OR"), -S(O) 2 (OR"), -SO 2NR"R 12 , halogen, (Ci-Cs)alkyl,

(C4-Cs)carbocyclylalkyl, (Ci-Cs)substituted alkyl, (C2-Cs)alkenyl, (C2-Cs)substituted alkenyl,

(C2-Cs)alkynyl, or (C2-Cs)substituted alkynyl.

[0080] In one embodiment of the method of treating a 2019-nCoV infection by administering

a compound of Formula II, R 1 of Formula II is H. In another aspect of this embodiment R 6 of

Formula II is N3, CN, halogen, (C-Cs)alkyl, (C-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-C)substituted alkenyl, (C2-C)alkynyl, or (C2-C)substituted alkynyl. In another aspect of

this embodiment, R 6 of Formula II is CN, methyl, ethenyl, or ethynyl. In another aspect of this

embodiment, R 6 of Formula II is CN. In another aspect of this embodiment, R 6 of Formula II is

methyl. In another aspect of this embodiment, R 5of Formula II is H. In another aspect of this

embodiment, R 2of Formula II is ORa. In another aspect of this embodiment, R2 of Formula II is

OH. In another aspect of this embodiment, R 2 of Formula II is F. In another aspect of this

embodiment, R 3of Formula II is ORa. In another aspect of this embodiment, R3 of Formula II is

OH, -OC(=O)R", or -OC(=)OR 1 .1 In another aspect of this embodiment, R 3 of Formula II is

OH. In another aspect of this embodiment, R8 of Formula II is NR1 1 R 12 . In another aspect of

this embodiment, R 8 of Formula II is NH 2 . In another aspect of this embodiment, R8 of Formula

II is OR". In another aspect of this embodiment, R 8of Formula II is OH. In another aspect of

this embodiment, R 9 of Formula II is H. In another aspect of this embodiment, R 9 of Formula II

is NR 1 R 1 2. Inanother aspect of this embodiment, R 9 of Formula II is NH2 . In another aspect of

this embodiment, R 7 of Formula II is H, -C(=)R", -C(=)OR1 1 or

0

zi'

In another aspect of this embodiment, R 7 of Formula II is H. In another aspect of this

embodiment, R 7 of Formula II is

0 11 ZP

z2

[0081] In another embodiment, provided is a method of treating a 2019-nCoV infection in a

compound of Formula I represented by Formula III:

R8

R7 N

0 0N N N R9

H R6 H H

R3 R2

Formula III

or a pharmaceutically acceptable salt or ester, thereof;

wherein

R 6 , R 7 , R 8 and R 9 are as defined above for Formula II;

each R 2 is ORa or F; and

each R3 is OR.

[0082] In one embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula III, R 6 of Formula III is N3, CN, halogen, (C1-C)alkyl,

(Ci-Cs)substituted alkyl, (C2-Cs)alkenyl, (C2-Cs)substituted alkenyl, (C2-Cs)alkynyl, or

(C2-C)substituted alkynyl. In another aspect of this embodiment, R 6 of Formula III is CN,

methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R 6 of Formula III is CN. In

another aspect of this embodiment, R 6 of Formula III is methyl. In another aspect of this

embodiment, R 2of Formula III is ORa. In another aspect of this embodiment, R2 of Formula III

is OH. In another aspect of this embodiment, R 2 of Formula III is F. In another aspect of this

embodiment, R 3 of Formula III is OH, -OC(=O)R", or -OC(=O)OR 1 1. In another aspect of this

embodiment, R 3 of Formula III is OH. In another aspect of this embodiment, R8 of Formula III

is NR 1 R 1 2. In another aspect of this embodiment, R of Formula III is NH 2 . In another aspect

of this embodiment, R 8 of Formula III is OR". In another aspect of this embodiment, R8 of

Formula III is OH. In another aspect of this embodiment, R 9 of Formula III is H. In another

aspect of this embodiment, R 9 of Formula III is NR1 1 R 1 2. In another aspect of this embodiment,

R 9 of Formula III is NH 2 . In another aspect of this embodiment, R 7 of Formula III is H,

-C(=O)R", -C(=O)OR 11 or

0

Zi

In another aspect of this embodiment, R 7 of Formula III is H. In another aspect of this

embodiment, R 7 of Formula III is

0

z2

[0083] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula III, R 6 of Formula III is N3, CN, halogen, (C-Cs)alkyl,

lit1

(C2-C8)substituted alkynyl and R 8 is NH2 . In another aspect of this embodiment, R 6 of Formula

III is CN, methyl, ethenyl, or ethynyl. In another aspect of this embodiment, R 6 of Formula III is

CN. In another aspect of this embodiment, R 6 of Formula III is methyl. In another aspect of this

is OH, -OC(=O)R", or -OC(=O)OR". In another aspect of this embodiment, R 2 of Formula III

embodiment, R 3 of Formula III is OH, -OC(=O)R", or -OC(=O)OR". In another aspect of this

embodiment, R 3 of Formula III is OH. In another aspect of this embodiment, R 9 of Formula III

is H. In another aspect of this embodiment, R 9 of Formula III is NR"R1 2 . In another aspect of

this embodiment, R 9 of Formula III is NH 2 . In another aspect of this embodiment, R 7 of

Formula III is H, -C(=)R", -C(=O)OR" or

0

z2

embodiment, R 7 of Formula III is

0 11 Zi z2

[0084] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula III, R 6 of Formula III is CN, methyl, ethenyl, or ethynyl,

R 8 is NH 2, and R 9 is H. In another aspect of this embodiment, R 6 of Formula III is CN. In

itS is OH. In another aspect of this embodiment, R 2 of Formula III is F. In another aspect of this embodiment, R 3 of Formula III is OH, -OC(=O)R", or -OC(=O)OR". In another aspect of this embodiment, R 3 of Formula III is OH. In another aspect of this embodiment, R 7 of Formula III is H, -C(=O)R", -C(=O)OR" or

0

z2

embodiment, R 7 of Formula III is

0

z2

[0085] In another embodiment, provided is a method of treating a 2019-nCoV infection in a

compound of Formula I represented by Formula IV:

NH 2

R7 N

N OH OH

Formula IV

or a pharmaceutically acceptable salt or ester, thereof;

wherein R 7 is as defined above for Formula I.

[0086] In some embodiments of the compounds of Formula I or Formula IV, Z4 is R,

C(Q2)Z1, or S0 2Z5 ;

Z5 is a carbocycle or a heterocycle;

each R 1 1 or R 12 is independently H, (C1-C)alkyl, (C2-C)alkenyl, (C2-C)alkynyl,

(C4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally substituted

heteroaryl, -C(=O)(C1-C)alkyl, -S(O).(C1-Cs)alkyl or (C-C20)aryl(C1-Cs)alkyl; or R"

and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7

membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can

optionally be replaced with -0-, -S- or -NH-; and wherein

each (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl or (C6-C20)aryl(C1-Cs)alkyl of each

R 2 , R 3 , R 5 , R, R 1 1or R 12 is, independently, optionally substituted with one or more halo,

hydroxy, CN, N3, NH 2 or OH; and wherein one or more of the non-terminal carbon atoms of

each said (C1-Cs)alkyl may be optionally replaced with -0-, -S- or -NH-.

[0087] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is H. In another embodiment of the method of

treating a 2019-nCoV infection comprising administering a compound of Formula IV, R 7 is

selected from the group of a), b), or c) as defined for Formula I.

[0088] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0 11

z2

wherein Z' and Z 2 are each, independently, a group having the structure:

,17

RY RY

~Q3- M12c

and Z 3 is Z5 .

[0089] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0 0o 0 0o HO-- HO HO - -# HO HOP - HO'PN"~~%~ HHO O I- P HO ,or

0 || /

z2

wherein Z' and Z 2 are each, independently, a group having the structure:

RQ RY

M12c

and Z 3 is Z5 .

[0090] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0 RX

3b

Rx

wherein each Q3b is, independently, 0 or N(R). In another embodiment, each Q3b is 0 and each

RX is independently:

Q3 Q3 R M12c

wherein M12c is 1, 2 or 3 and each Q 3 is independently a bond, 0, CR 2, or S.

[0091] In some embodiments, R° and Re2 can each independently be H, C1-C6 alkyl or benzyl.

In some embodiments, R° can be H, C1-C6 alkyl or benzyl, and Re2 can be H or C1-C6 alkyl. In

some embodiments, R° and Re2 can each independently be H or C1-C6 alkyl. In some

embodiments, R° and Re2 can each independently be H or benzyl. In some embodiments, R°

can be H, methyl or benzyl, and Re2 can be H or methyl. In some embodiments, R° can be H or

methyl, and Re2 can be H or methyl. In some embodiments, R° can be methyl, and Re2 can be H

or methyl. In some embodiments, R° can be H or benzyl, and Re2 can be H or methyl.

[0092] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

-(RY)o-3

09 0 \ " CH 3 OR H 0

[0093] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0 00 0o HO--P-- P SHO- P / HO O HO HO HO

A1O o 0 -P 0' NH r R RSe

[0094] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0O CH 3 \ O CH 3

N OR HOR'

0 or 0

wherein Rf is selected from the group of from H, C1-C8 alkyl, benzyl, C3-C cycloalkyl, and

-CH 2-C 3-C 6cycloalkyl. In another embodiment of a compound of Formula IV, Rf is C1-C8 alkyl.

In another embodiment of a compound of Formula IV, Rf is 2-ethylbutyl.

[0095] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

HO-P # ~ HO--P # P, ,P #

HO 0P / - HO H HO , HO HO- H

0~. < 0" /"', I 00 HOP 0 o0H H0

Rg 0 1 or RR o NH orRO NH

wherein

Rf is selected from H, C1-C8 alkyl, benzyl, C3-C cycloalkyl, and -CH 2 -C 3 -C6 cycloalkyl; and

Sn

R9 is selected from C1-C8 alkyl, -0-C1-C8 alkyl, benzyl, -O-benzyl,-CH2 -C 3 -C6 cycloalkyl, -0

CH 2 -C 3 -C 6 cycloalkyl, and CF 3

.

[0096] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0 O-P - O-P RO NH or R NH

wherein Rf is selected from H, C1-C8 alkyl, benzyl, C3-C6 cycloalkyl, and -CH 2 -C 3 -C

cycloalkyl. In another embodiment of a compound of Formula IV, Rf is C1-C8 alkyl. In another

embodiment of a compound of Formula IV, Rf is C1-C6 alkyl. In another embodiment of a

compound of Formula IV, Rf is 2-ethylbutyl.

[0097] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R7 is:

0 R9

0 S

wherein R9 is selected from C1-C8 alkyl, -- C1-C8 alkyl, benzyl, -- benzyl, -CH 2 -C 3 -C

cycloalkyl, -O-CH 2-C 3-C cycloalkyl, and CF 3. In another embodiment of a compound of

Formula IV, Rf is Ci-C8 alkyl. In another embodiment of a compound of Formula IV, Rf is Ci

C6 alkyl.

[0098] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is selected from the group of:

0 0 0 0 0 HO - HO- HO H O HO HO HO

[0099] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, R 7 is

0 00 0o HO--HO/0/ P_ #P - HO O HO HO , H HO

O O O

SY 0 O-P-OP 0

000 0 ., Ok NH -- ' o TNH "X O

O-P- O-P-1 OO

O NH or NH

[0100] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, Z' and Z 2 can each be:

RY RY

Sk Q3- 'Ry M12c

[0101] In another embodiment, provided is a method of treating a 2019-nCoV infection in a

compound of Formulas I-IV, wherein R" or R 12 is independently H, (C1-C8)alkyl,

(C2-C)alkenyl, (C2-C)alkynyl, (C4-C)carbocyclylalkyl, optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-Cs)alkyl, -S(O).(C1-C)alkyl or aryl(C1-Cs)alkyl. In another

embodiment, R" and R 12 taken together with a nitrogen to which they are both attached, form a

3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can

optionally be replaced with -0-, -S- or -NRa-. Therefore, by way of example and not limitation,

the moiety -NR"R 12 can be represented by the heterocycles:

-N0-N" O -N S -N NRa - -N a

and the like.

[0102] In another embodiment, provided is a method of treating a 2019-nCoV infection in a

compound of Formula I-IV, wherein each R3 , R4 , R', R,R1 1 orR1 2 is, independently,

(C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-C)alkynyl or aryl(C1-Cs)alkyl, wherein said (C1-C)alkyl,

(C2-C)alkenyl, (C2-C)alkynyl or aryl(C1-C)alkyl are, independently, optionally substituted

with one or more halo, hydroxy, CN, N3, N(Ra) 2 or ORa. Therefore, by way of example and not

limitation, R 3 , R 4 , R', R6, R" or R 12 could represent moieties such as -CH(NH 2 )CH3 ,

--CH(OH)CH 2CH 3, -CH(NH 2)CH(CH 3) 2 , -CH 2CF3 , -(CH 2) 2CH(N 3 )CH3 , -(CH 2) 6NH 2 and the

like.

[0103] In another embodiment, provided is a method of treating a 2019-nCoV infection in a

compound of Formula I-IV, wherein R 3 , R 4 , R', R6, R" or R 12 is (C1-Cs)alkyl wherein one or

more of the non-terminal carbon atoms of each said (C1-Cs)alkyl may be optionally replaced

with -0-, -S- or -NRa-. Therefore, by way of example and not limitation, R 3, R4 , R', R6, R" or

R 12 could represent moieties such as -CH2 0CH 3, -CH2 0CH 2CH3 , -CH20CH(CH 3) 2 , -CH 2SCH 3

, -(CH 2) 6 0CH3 , -(CH 2) 6N(CH 3 )2 and the like.

[0104] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula I, the compound is

NH 2 NH 2 N NN N0 H N N O O-P-O N HO -, ' NH HO-H H OH O Hd oH

NH 2 NH 2 N N, N

OO-P-O OO-- 0 0 NH OH H OH

NH 2 N 0 0 N. N O HN-P-O NH N HO OH

NH 2 NH 2 S N N o-P-O N'N 11 11 11 NN, 0 0 S 'CN H OH O"CN Hd OH , and Hd OH

or a pharmaceutically acceptable salt or ester thereof.

Si1

[0105] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula I, the compound is

NH 2

NH 2 N 11 ~\ N , 1) NN S O- -O O N HO \N,< 0 '0 ""N HON HO N 'CN Hd oH HO H 0

NH 2 NH 2

NN OQ 10 O O-P-O 0 OO N 0-'N H N

NH2

NH 2 N N 0--O .'CNN

OO O-P-OG

O NH HO oHN 0O 0 WC'N 0 NH 2 NH 2 00 OHP

-ON PhO-P-O O

NH HO OH O N~

0- -O O 'N P O -O 0 00 NH 2 NH2

H0 H N O NHH 'N

NH 2 0 NH 2 N0 H N O NO N _' . O N'O O NN 00 NH HO CNN

O NH 2 NH 2

O ,ON ~ 0 NO N

N'N HOH bH Hd H o N, 0 r\N 0O N N N O- N

O HE00 "H NH N 2 0 HNG NH 2

0-P--ON SN NH

NH 2 NH 2 NN

0 HNP-O 0 HN--P-O A 0 N 0 0 N HO OH HO OH

or apharmaceutically acceptable salt or ester thereof.

[0106] In another embodiment of the method of treating a2019-nCoV infection comprising

administering acompound of Formula IV, the compound is:

NH 2 NH 2

- N N, N N N N- HO -, O 'CN NH HN HO H0U OH OHO 6oH

" NH 2 NH 2 N N

9 O N, N) NI) O O-P-O 11 O N NO O-P1 0 Ok NH HO H H NH H N

NH 2

N

h, _ O N \ N O HN-P-O NH -. N HOO

NH2 NH 2 S N 11 N PP S'N HO' O'HO6HO 0ON

Hd aH '' H , or Hd OH

or a pharmaceutically acceptable salt or ester thereof.

[0107] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula IV, the compound is:

NH 2

NH 2 N N

N S O- -O O NN

HON S N HO 'CN ON Hd oH HO bH 0l\

NH 2 NH 2

N NN SO-0- -N

O NH HO OH NO NH HO OHN

o-P-o0 NH2

-- N H HO OH

N d o O or

or apharmaceutically acceptable salt or ester thereof.

[0108] In another embodiment of the method of treating a2019-nCoV infection comprising

administering acompound of FormulaJI-IV, the compound is

NH 2 NH 2

-- 0 N -

oo-P-o •, T 0O-P-O NH H OH NNH H OHN

NH 2 90 0 NNH 2

O HOH0 NON NH H1 0OH

. NH 2 NH 2

0 N --

PhO-P-O_ \NN< O-P - N N 0 N 0NH

00 0 OH 00 HO OH

NH 2 NH 2

90 N K0 0) 11 ON, N 0 P 'O 10 N, N O 1- o1 NH :' 1 NH Hz OH

0 NH 2 oNH 2 H N 0 HN N0 o N 01 N0,N

'-~N 6 Hd -'0H b Hd - ~H

Q 0o NH 2 ~ 0 NH 2

0 0 0 r\N

'N b Hd bJH OO

0 HE5

NH 2

0 O- N I "CN NH N HO OH

NH 2 NH 2

N N

0 'N O N'N SHNI".P-O HN-P-O A . N 0 z S N HO OH HO OH

or C

or a pharmaceutically acceptable salt or ester thereof.

[0109] In another embodiment of the method of treating a 2019-nCoV infection comprising

administering a compound of Formula I-IV, the compound is

NH 2 NH 2

0N N ON 0\ 0 \NJ O N'N O1N' o HNI".P- 0 0 N, HN--P-O A . N 0 z S N HO OH 0 HO H

or C

or a pharmaceutically acceptable salt or ester thereof. In another embodiment of the method of

treating a 2019-nCoV infection comprising administering a compound of Formula I-IV, the

compound is

NH 2

0 ~N

o HN-P-O A

' HO OH

or a pharmaceutically acceptable salt or ester

thereof.

[0110] The method described herein can be used to treat COVID-19 caused by any strain of

the SARS-CoV-2. For example, in some embodiments, the methods described herein are useful

in treating infections caused by type L or type S of the SARS-CoV-2. In some embodiments, the

methods described herein are useful in treating infections caused by type L of the SARS-CoV-2.

In some embodiments, the methods described herein are useful in treating infections caused by

type S of the SARS-CoV-2. In some embodiments, the methods described herein are useful in

treating infections caused by UK SARS-CoV-2 B.1.1.7 or South Africa SARS-CoV-2 501.V2.

[0111] The methods described herein can be used to treat viral infections caused by viruses

having polymerase homologous to the SARS polymerase. For example, the methods can be used

to treat viral infections caused by virus having at least about 60% sequence homology to the

SARS polymerase. In some embodiments, the methods described herein are used to treat viral

infections caused by a virus having at least 70%, at least 75%, at least 80%, at least 85%, at least

%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence homology

to the SARS polymerase. In some embodiments, the methods described herein are used to treat

viral infections caused by a virus having at least 90% sequence homology to the SARS

polymerase. In some embodiments, the methods described herein are used to treat viral

infections caused by a virus having at least 92% sequence homology to the SARS polymerase.

In some embodiments, the methods described herein are used to treat viral infections caused by

a virus having at least 94% sequence homology to the SARS polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by a virus having at least

96% sequence homology to the SARS polymerase. In some embodiments, the methods

described herein are used to treat viral infections caused by a virus having at least 98% sequence

homology to the SARS polymerase. In some embodiments, the methods described herein are

used to treat viral infections caused by a virus having at least 99% sequence homology to the

SARS polymerase. In some embodiments, the polymerase is RNA dependent RNA polymerase.

[0112] In some embodiments, the methods described herein are used to treat viral infections

caused by a virus having at least 90% sequence homology to the type L SARS-CoV-2

infections caused by a virus having at least 92% sequence homology to the type L SARS-CoV-2

infections caused by a virus having at least 94% sequence homology to the type L SARS-CoV-2

infections caused by a virus having at least 96% sequence homology to the type L SARS-CoV-2

infections caused by a virus having at least 98% sequence homology to the type L SARS-CoV-2

infections caused by a virus having at least 99% sequence homology to the type L SARS-CoV-2

polymerase. In some embodiments, the polymerase is RNA dependent RNA polymerase.

[0113] In some embodiments, the methods described herein are used to treat viral infections

caused by a virus having at least 90% sequence homology to the type S SARS-CoV-2

infections caused by a virus having at least 92% sequence homology to the type S SARS-CoV-2

infections caused by a virus having at least 94% sequence homology to the type S SARS-CoV-2

Al polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by a virus having at least 96% sequence homology to the type S SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by a virus having at least 98% sequence homology to the type S SARS-CoV-2 polymerase. In some embodiments, the methods described herein are used to treat viral infections caused by a virus having at least 99% sequence homology to the type S SARS-CoV-2 polymerase. In some embodiments, the polymerase is RNA dependent RNA polymerase.

[0114] In some embodiments, the methods can be used to treat viral infections caused by a

virus having at least about 60% sequence homology to the whole genome sequence of SARS

CoV-2. For example, the methods described herein are used to treat viral infections caused by a

virus having at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at

least 96%, at least 97%, at least 98%, or at least 99% sequence homology to the whole genome

sequence of SRAS-CoV-2. In some embodiments, the methods described herein are used to treat

viral infections caused by a virus having at least 90% sequence homology to the whole genome

viral infections caused by a virus having at least 92% sequence homology to the whole genome

viral infections caused by a virus having at least 94% sequence homology to the whole genome

viral infections caused by a virus having at least 96% sequence homology to the whole genome

viral infections caused by a virus having at least 98% sequence homology to the whole genome

viral infections caused by a virus having at least 99% sequence homology to the whole genome

sequence of SRAS-CoV-2.

[0115] Names of compounds of the present disclosure are provided using ACD/Name

software for naming chemical compounds (Advanced Chemistry Development, Inc., Toronto,

Canada). Other compounds or radicals may be named with common names or systematic or

non-systematic names. The naming and numbering of the compounds of the disclosure is

illustrated with a representative compound of Formula I:

NH 2

NH HN o HO OH

which is named (2S)-2-ethylbutyl 2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin

7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propano

ate. Other compounds of the present invention include:

NH 2

N O N'N o HN-P-O AN HO OH

which is named (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1

f][1,2,4]triazin

7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propan

oate, and

NH 2

0 N

O 0 O N' N o HN-P-O

O HO OH

which is named (S)-2-ethylbutyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1

f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2

yl)methoxy)(phenoxy)phosphoryl)amino)propanoate.

[0116] Any reference to the compounds of the invention described herein also includes a

reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable

salts of the compounds of the invention include salts derived from an appropriate base, such as

an alkali metal or an alkaline earth (for example, Na+, Li+, K+, Ca+ 2 and Mg+ 2 ), ammonium

and NR 4+ (wherein R is defined herein). Physiologically acceptable salts of a nitrogen atom or

an amino group include (a) acid addition salts formed with inorganic acids, for example,

hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid

and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid,

tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid,

ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic

acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,

benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid,

sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid,

phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid,

glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from

elemental anions for example, chlorine, bromine, and iodine. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na+ and NR4 +.

[0117] A compound of Formula I-IV and its pharmaceutically acceptable salts may exist as

different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means

the ability of a crystalline compound to exist in different crystal structures. The crystalline

polymorphism may result from differences in crystal packing (packing polymorphism) or

differences in packing between different conformers of the same molecule (conformational

polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate

or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the

instant invention may exist due to differences in crystal packing (packing pseudopolymorphism)

or due to differences in packing between different conformers of the same molecule

(conformational pseudopolymorphism). The instant invention comprises all polymorphs and

pseudopolymorphs of the compounds of Formula I-III and their pharmaceutically acceptable

salts.

[0118] A compound of Formula I-IV and its pharmaceutically acceptable salts may also exist

as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long

range order of the positions of the atoms in the solid. This definition applies as well when the

crystal size is two nanometers or less. Additives, including solvents, may be used to create the

amorphous forms of the instant invention. The instant invention comprises all amorphous forms

of the compounds of Formula I-IV and their pharmaceutically acceptable salts.

[0119] For therapeutic use, salts of active ingredients of the compounds of the invention will

be physiologically acceptable, i.e. they will be salts derived from a physiologically acceptable

acid or base. However, salts of acids or bases which are not physiologically acceptable may also

find use, for example, in the preparation or purification of a physiologically acceptable

AA;-- compound. All salts, whether or not derived from a physiologically acceptable acid or base, are within the scope of the present invention.

[0120] Finally, it is to be understood that the compositions herein comprise compounds of the

invention in their un-ionized, as well as zwitterionic form, and combinations with stoichiometric

amounts of water as in hydrates.

[0121] It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers,

polymorphs, pseudopolymorphs of compounds within the scope of Formula I-IV and

pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures

of such enantiomers and diastereomers are within the scope of the present invention.

[0122] The compounds of the invention, exemplified by Formula I-IV may have chiral

centers, e.g. chiral carbon or phosphorus atoms. The compounds of the invention thus include

racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers.

In addition, the compounds of the invention include enriched or resolved optical isomers at any

or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions

are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric

mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of

their enantiomeric or diastereomeric partners, are all within the scope of the invention. The

racemic mixtures are separated into their individual, substantially optically pure isomers through

well-known techniques such as, for example, the separation of diastereomeric salts formed with

optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active

substances. In most instances, the desired optical isomer is synthesized by means of

stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting

material.

[0123] Stereochemical definitions and conventions used herein generally follow S. P. Parker,

Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New

York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley

& Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have

the ability to rotate the plane of plane-polarized light. In describing an optically active

compound, the prefixes D and L or R and S are used to denote the absolute configuration of the

molecule about its chiral center(s). The prefixes d and 1, D and L, or (+) and (-) are employed to

designate the sign of rotation of plane-polarized light by the compound, with S, (-), or 1 meaning

that the compound is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory.

For a given chemical structure, these stereoisomers are identical except that they are mirror

images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a

mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of

enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has

been no stereoselection or stereospecificity in a chemical reaction or process. The terms

racemicc mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species,

devoid of optical activity.

[0124] The compounds of the invention can also exist as tautomeric isomers in certain cases.

Although only one delocalized resonance structure may be depicted, all such forms are

contemplated within the scope of the invention. For example, ene-amine tautomers can exist for

purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and all their possible

tautomeric forms are within the scope of the invention.

[0125] Any formula or structure given herein, including Formula I compounds, is also

intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.

Isotopically labeled compounds have structures depicted by the formulas given herein except

that one or more atoms are replaced by an atom having a selected atomic mass or mass number.

Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes

of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not

limited to 2H (deuterium, D),3 H (tritium), C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 p, 35, 36C1 and 125

Various isotopically labeled compounds of the present disclosure, for example those into which

radioactive isotopes such as 3H, 1 3 C and 14 C are incorporated. Such isotopically labelled

compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging

techniques, such as positron emission tomography (PET) or single-photon emission computed

tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive

treatment of patients.

[0126] The disclosure also included compounds of Formula I in which from 1 to n hydrogens

attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens

in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful

for increasing the half-life of any compound of Formula I when administered to a mammal,

particularly a human. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug

Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized

by means well known in the art, for example by employing starting materials in which one or

more hydrogens have been replaced by deuterium.

[0127] Deuterium labeled or substituted therapeutic compounds of the disclosure may have

improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution,

metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may

afford certain therapeutic advantages resulting from greater metabolic stability, for example

increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic

index. An 18F labeled compound may be useful for PET or SPECT studies. Isotopically labeled

compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the

procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I.

[0128] The concentration of such a heavier isotope, specifically deuterium, may be defined by

an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically

designated as a particular isotope is meant to represent any stable isotope of that atom. Unless

otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is

understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the

compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to

represent deuterium.

[0129] Whenever a compound described herein is substituted with more than one of the same

designated group, e.g., "R" or "Rl", then it will be understood that the groups may be the same

or different, i.e., each group is independently selected. Wavy lines, - , indicate the site of

covalent bond attachments to the adjoining substructures, groups, moieties, or atoms.

[0130] Selected substituents comprising the compounds of Formula I-IV are present to a

recursive degree. In this context, "recursive substituent" means that a substituent may recite

another instance of itself. Because of the recursive nature of such substituents, theoretically, a

large number of compounds may be present in any given embodiment. For example, RX

comprises a R substituent. R can be R. R can be Z 3. Z 3 can be Z4 and Z 4 can be R or

comprise substituents comprising Ry. Alternatively, Z 3 can be Z 5 which can comprise

substituents comprising Ry. One of ordinary skill in the art of medicinal chemistry understands

that the total number of such substituents is reasonably limited by the desired properties of the

compound intended. Such properties include, by way of example and not limitation, physical

'n properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

[0131] By way of example and not limitation, Z 3 and R are recursive substituents in certain

embodiments. Typically, each recursive substituent can independently occur 20, 19, 18, 17, 16,

, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment. More typically,

each recursive substituent can independently occur 12 or fewer times in a given embodiment.

Even more typically, each recursive substituent can independently occur 3 or fewer times in a

given embodiment. For example, Z 3 will occur 0 to 8 times, R will occur 0 to 6 times in a

given embodiment. Even more typically, Z 3 will occur 0 to 6 times and R will occur 0 to 4

times in a given embodiment.

[0132] Recursive substituents are an intended aspect of the invention. One of ordinary skill in

the art of medicinal chemistry understands the versatility of such substituents. To the degree

that recursive substituents are present in an embodiment of the invention, the total number will

be determined as set forth above.

[0133] The compounds of the present invention can be prepared by methods known to one of

skill in the art. For example, the compounds of the present invention can be prepared according

to the methods described in U.S. Patent No. 8,008,264 and U.S. Application Publication No.

US 2012/0027752.

1. Substituted Forms of the Compounds

[0134] The compounds of the Formula I-IV may comprise a phosphate group as R 7 , R 7 is

selected from the group of

a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R", -S(O) 2 R",

-S(O)(OR 11 ), -S(O) 2 (OR"), -S 2 NR"R 12

wherein

'71 each R1 1 or R 12 is independently H, (C1-C)alkyl, (C2-C)alkenyl, (C2-C)alkynyl,

(C4-Cs)carbocyclylalkyl, optionally substituted aryl, optionally substituted

heteroaryl, -C(=O)(C1-Cs)alkyl, -S(O).(C1-C)alkyl or aryl(C1-Cs)alkyl; or R"

and R 12 taken together with a nitrogen to which they are both attached form a 3 to

7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic

ring can optionally be replaced with -0-, -S- or -NRa_

each Ra is independently H, (C1-Cs)alkyl, (C2-C)alkenyl, (C2-C)alkynyl,

aryl(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, -C(=O)R, -C(=O)OR, -C(=O)NR 2

, -C(=O)SR, -S(O)R, -S(O) 2 R, -S(O)(OR), -S(O) 2 (OR), or -SO 2 NR 2 ;

wherein each R is independently H, (C-Cs) alkyl, (C-Cs) substituted alkyl,

(C2-C)alkenyl, (C 2 -Cs) substituted alkenyl, (C 2 -Cs) alkynyl, (C 2 -Cs) substituted

alkynyl, C6-C20 aryl, C6-C20 substituted aryl, C2-C2 heterocyclyl, C2-C20

substituted heterocyclyl, arylalkyl or substituted arylalkyl; and

wherein each (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-C)alkynyl or aryl(C1-Cs)alkyl of each

R" or R 12 is, independently, optionally substituted with one or more halo,

hydroxy, CN, N3, N(Ra) 2 or ORa; and wherein one or more of the non-terminal

carbon atoms of each said (C1-Cs)alkyl may be optionally replaced with -0-, -S

or -NRa_

b)

0 0 0 O 0 HO--P

HO / 0 HO HO HO HO or HO ; c)

Rc 0 Rc So. el 0-P

/ el0-P

R Rd e2 'Rd (CH 2 )n (CH2 )n'

/ O / 0 R, Rf or R9 R9

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl,

N

and;

Rd is H or CH 3;

R° and Re2 are each independently H, C1-C6 alkyl or benzyl;

Rf is selected from H, C-C8 alkyl, benzyl, C3-C cycloalkyl, and -CH 2 -C 3-C

cycloalkyl;

R9 is selected from C1-C8 alkyl,-0-c-Calkyl, benzyl, -O-benzyl,-CH2 -C3 -C

cycloalkyl, -O-CH 2-C 3-C 6 cycloalkyl, and CF3; and

n' is selected from 1, 2, 3, and 4; and

d) a group of the formula:

Q

P Z1 z2

wherein

Q is 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR 2;

Z' and Z2 , when taken together, are -Q'(C(RY)2)3Q -

wherein

each Q 1 is independently 0, S, or NR; and

each R is independently H, F, Cl, Br,I, OH, R, -C(=Q 2)R, -C(=Q 2)OR,

-C(=Q2)N(R)2, -N(R)2, -+N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)(OR),

-S(O)2(OR), -OC(=Q2)R, -OC(=Q2)OR, -OC(=Q2)(N(R)2), -SC(=Q2)R,

-SC(=Q2)OR, -SC(=Q2)(N(R)2), -N(R)C(=Q2)R, -N(R)C(=Q2)OR,

-N(R)C(=Q 2)N(R) 2 , -SO2 NR2 , -CN, -N3, -N02, -OR, or Z3; or when

taken together, two R on the same carbon atom form a carbocyclic ring

of 3 to 7 carbon atoms;

each Q 2 is independently, 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR2;or

Z' and Z2 are each, independently, a group of the Formula Ia:

Q2

RX Q3 p3__

Q3

RX M2

Formula Ia

wherein:

each Q 3 is independently a bond, 0, CR 2 , NR, 'N(O)(R), N(OR), 'N(O)(OR),

N-NR 2 , S, S-S, S(O), or S(O)2;

M2 is 0, 1 or 2;

each RX is independently R or the formula:

'7,

Q2 RY RY Q2

R~ _RY Q3' Q 3 YJ 2 M2cd Mia M1c

wherein:

each Mla, Mlc, and Mid is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

ZI is Z 4 or Z5;

Z4 is R,-C(Q 2 )Ry, -C(Q 2 )Z5 , -SO 2 RY, or -S0 2Z5 ; and

Z 5 is a carbocycle or a heterocycle wherein Z5 is independently

substituted with 0 to 3 R groups.

[0135] Z 5 carbocycles and Z 5 heterocycles may be independently substituted with 0 to 3 R

groups. Z5 may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic

carbocycle or heterocycle. Z 5 may have 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The Z5 rings

are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4

ring atoms, saturated, or mono- or di-unsaturated when containing 5 ring atoms, and saturated,

mono- or di-unsaturated, or aromatic when containing 6 ring atoms.

[0136] A Z5 heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms

and 1 to 3 heteroatoms selected from N, 0, P, and S) or a bicycle having 7 to 10 ring members

(4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, 0, P, and S). Z5 heterocyclic

monocycles may have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected

from N, 0, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected

from N and S). Z5 heterocyclic bicycles have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2

heteroatoms selected from N, 0, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system;

or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system. The Z5 heterocycle may be bonded to Q 2 through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.

[0137] Z 5 heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine,

pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl,

pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. Z5 also includes, but is not

limited to, examples such as:

N H (N N H

, and

[0138] Z 5 carbocycles and heterocycles may be independently substituted with 0 to 3 R

groups, as defined above. For example, substituted Z5 carbocycles include:

OH CI N -\ / OH \ CI

N O NH 2

7A-

O NH - NH NH

?-N O ?-N S -N SO 2

[0139] Examples of substituted phenyl carbocycles include:

HN NH 2 -HN NMe 2 - NH 2

0 0 0 0 \-NH _-°°o - NH NH2 NH2 NH2

[0140] In another embodiment, Z 5 of the compounds of Formula I-IV is a carbocycle or a

heterocycle wherein Z 5 is independently substituted with 0 to 3 Rz groups, wherein each Rz is

independently H, F, Cl, Br,I, OH, R, -C(=Q 2)R, -C(=Q 2)OR, -C(=Q 2)N(R) 2, -N(R) 2, -+N(R) 3 ,

-SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -OC(=Q')R, -OC(=Q2)OR, -OC(=Q2)(N(R)2),

-SC(=Q2)R, -SC(=Q2)OR, -SC(=Q2)(N(R)2), -N(R)C(=Q2)R, -N(R)C(=Q2)OR,

-N(R)C(=Q 2)N(R) 2 , -SO2 NR2 , -CN, -N3, -N02, or -OR.

Q

zi-y/

[0141] Embodiments of z2 of Formula I-IV compounds include substructures

such as:

Rx

3b

RX

wherein each Q3b is, independently, 0 or N(R). In another aspect of this embodiment, each Q3

is 0 and each R is independently:

0

Q3 Q3 R M12c

wherein M12c is 1, 2 or 3 and each Q3 is independently a bond, 0, CR 2, or S. In another aspect

of this embodiment, one Q 3 -R' is NH(R) and the other Q3 -R' is O-R' wherein RX is:

R R 0

1-~'S -'CR3 M12c

wherein M12c is 2. In another aspect of this embodiment, each Q3b is 0 and each RX is

independently:

R R 0

1-~'S -'CR3 M12c

independently:

R R 1----~'' oQ 3 R M12c

wherein M12c is 1 and Q3 is a bond O, or CR 2

. Q

[0142] Other embodiments of z2 of Formulas I-IV compounds include

substructures such as:

RY

Q3 R II P RY \ 3 RY

Ry RY

wherein each Q3 is, independently, 0 or N(R). In another aspect of this embodiment, each Q3 is 0. In another aspect of this embodiment, the substructure is:

0/ 0

0

RY

wherein R is Z5 as defined herein.

Q P -- '

[0143] Another embodiment of z2 of Formula I-IV includes the substructures:

'70

R

0 Q3 || RY 0

3 5 Q c-Z

wherein each Q2e is, independently, 0, N(RY) or S.

Q

[0144] Another embodiment of z2 of Formula I-IV compounds includes the

substructures wherein one of Z' or Z 2 together with either R 3 or R 4 is -Q 3- and the other of Z' or

Z 2 is Formula Ia. Such an embodiment is represented by a compound of Formula Ib selected

from:

0-H 2 0 Base O-CH 2 Base

RQ R1 R6 RQ R1 R6 Q3 Q3 4 2 R R R3 R2

Z2 20---CH2 2 0----H2 Base z O Base 5 R P R5 R R6 R Qi Q3 Q3 2 R 3 R or R4 R2

Formula Ib

[0145] In another aspect of the embodiment of Formula Ib, each Q and Q3 is 0. In another

aspect of the embodiment of Formula Ib, Z' or Z2 is Q 3b-R; each Q, Q 3 and Q3b is 0 and RX is:

9n

Q3 Q3 R M12c

of the embodiment of Formula Ib, Z or Z 2 is Q 3b-R; each Q, Q3 and Q3b is 0 and Ris:

R R 0

S _'CR3 M12c

wherein M12c is 2. In another aspect of the embodiment of Formula Ib, Z or Z 2 is Q3 -R; each

Q, Q 3 and Q 3b is O and Rx is:

R R 0

OQ 3

M12c

wherein M2cis 1and Q 3 is abond,0,or CR2 .

Q

[0146] Another embodiment of z2 of Formula I-IV compounds includes a

substructure:

Rx

3b

RX

wherein Z5 is a carbocycle such as phenyl or substituted phenyl. In another aspect of this

embodiment, the substructure is:

(RY)0-3

0 \\0 Ry

\Q3b OR

0

wherein Q3bis 0 or N(R) and the phenyl carbocycle is substituted with 0 to 3 R groups. In

another aspect of this embodiment of the substructure, R is:

0

Q3 Q3 R M12c

wherein M12c is 1, 2 or 3 and each Q3 is independently a bond, 0, CR 2, or S.

Q

[0147] Another embodiment of z2 of Formula I-IV includes substructures:

\(R)G-3 0(R)o-3

O C\\O CH 3

H OR OOR

o and O

[0148] The chiral carbon of the amino acid and lactate moieties may be either the R or S

configuration or the racemic mixture.

Q

[0149] Another embodiment of z2 of Formula I-IV is substructure

R

11 ORY 1_ P- Q3 0

2

wherein each Q3 is, independently, -0- or -NH-. In another aspect of this embodiment, R is

(C 1-Cs) alkyl, (C 1 -Cs) substituted alkyl, (C 2 -Cs) alkenyl, (C 2 -Cs) substituted alkenyl, (C 2 -Cs)

alkynyl or (C 2 -Cs) substituted alkynyl. In another aspect of this embodiment, R is (C1 -Cs)

alkyl, (C 1 -Cs) substituted alkyl, (C 2 -Cs) alkenyl, (C 2 -Cs) substituted alkenyl, (C 2 -Cs) alkynyl or

(C 2 -Cs) substituted alkynyl; and R is CH 3 . In another aspect of this embodiment, R is (C1-Cs)

alkyl, (C1-Cs) substituted alkyl, (C2-Cs) alkenyl, (C2-Cs) substituted alkenyl, (C2-Cs) alkynyl or

(C2-Cs) substituted alkynyl; R is CH3 ; and each Q3 is -NH-. In another aspect of this

embodiment, Z' and Z2 are, independently, nitrogen-linked, naturally occurring amino acids or

naturally occurring amino acid esters. In another aspect of this embodiment, Z' and Z 2 are, independently, naturally-occurring 2-hydroxy carboxylic acids or naturally-occurring 2-hydroxy carboxylic acid esters wherein the acid or ester is linked to P through the 2-hydroxy group.

Q

[0150] Another embodiment of z2 of Formula I-IV is substructure:

0 Rx

Rx

[0151] In one aspect of this embodiment, each RX is, independently, (C1-C 8) alkyl. In another

aspect of this embodiment, each RX is, independently, C-C20 aryl or C-C20 substituted aryl.

[0152] In an embodiment,

0

2 z

is selected from

SZM

0 0 LNHR OSC(R)3 P

R R O - S -S

- t / C(R)3 .R C(R)3 O H RRR O O

HO R

CH3 P

O

(RY)n or z5

[0153] Embodiments of R' include esters, carbamates, carbonates, thioesters, amides,

thioamides, and urea groups:

R R R R 0 Q2

R3 1 3RY QN'RY Q Y M12a Q2 and M12a

2. Metabolites of the Compounds of the Invention

[0154] Also falling within the scope of this invention are the in vivo metabolic products of the

compounds described herein, to the extent such products are novel and unobvious over the prior

art. Such products may result for example from the oxidation, reduction, hydrolysis, amidation,

esterification and the like of the administered compound, primarily due to enzymatic processes.

Accordingly, the invention includes novel and unobvious compounds produced by a process

comprising contacting a compound of this invention with a mammal for a period of time

sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. 1 4 C or 3H) compound of the invention, administering it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur

(typically about 30 seconds to 30 hours) and isolating its conversion products from the urine,

blood or other biological samples. These products are easily isolated since they are labeled

(others are isolated by the use of antibodies capable of binding epitopes surviving in the

metabolite). The metabolite structures are determined in conventional fashion, e.g. by MS or

NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug

metabolism studies well-known to those skilled in the art. The conversion products, so long as

they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the

compounds of the invention even if they possess no anti 2019-nCoV activity of their own.

[0155] Recipes and methods for determining stability of compounds in surrogate

gastrointestinal secretions are known. Compounds are defined herein as stable in the

gastrointestinal tract where less than about 50 mole percent of the protected groups are

deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37 °C. Simply

because the compounds are stable to the gastrointestinal tract does not mean that they cannot be

hydrolyzed in vivo. The prodrugs of the invention typically will be stable in the digestive

system but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver or

other metabolic organ, or within cells in general.

3. PHARMACEUTICAL FORMULATIONS

[0156] The compounds of this invention are formulated with conventional carriers and

excipients, which will be selected in accord with ordinary practice. Tablets will contain

excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile

form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the

"Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other

antioxidants, chelating agents such as EDTA, carbohydrates such as dextran,

hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the

formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. In some

embodiments, the pH of the formulations ranges from about 2 to about 5, but is ordinarily about

3 to 4.

[0157] While it is possible for the active ingredients to be administered alone it may be

preferable to present them as pharmaceutical formulations. The formulations, both for

veterinary and for human use, of the invention comprise at least one active ingredient, as above

defined, together with one or more acceptable carriers therefor and optionally other therapeutic

ingredients, particularly those additional therapeutic ingredients as discussed herein. The

carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the

formulation and physiologically innocuous to the recipient thereof.

[0158] The formulations include those suitable for the foregoing administration routes. The

formulations may conveniently be presented in unit dosage form and may be prepared by any of

the methods well known in the art of pharmacy. Techniques and formulations generally are

found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such

methods include the step of bringing into association the active ingredient with the carrier which

constitutes one or more accessory ingredients. In general the formulations are prepared by

uniformly and intimately bringing into association the active ingredient with liquid carriers or

finely divided solid carriers or both, and then, if necessary, shaping the product.

[0159] Formulations of the present invention suitable for oral administration may be presented

as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

[0160] A tablet is made by compression or molding, optionally with one or more accessory

ingredients. Compressed tablets may be prepared by compressing in a suitable machine the

active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a

binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets

may be made by molding in a suitable machine a mixture of the powdered active ingredient

moistened with an inert liquid diluent. The tablets may optionally be coated or scored and

optionally are formulated so as to provide slow or controlled release of the active ingredient

therefrom.

[0161] For infections of the eye or other external tissues e.g. mouth and skin, the formulations

are preferably applied as a topical ointment or cream containing the active ingredient(s) in an

amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between

0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to

% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active

ingredients may be employed with either a paraffinic or a water-miscible ointment base.

Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream

base.

[0162] If desired, the aqueous phase of the cream base may include, for example, at least 30%

w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as

propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol

(including PEG 400) and mixtures thereof. The topical formulations may desirably include a

compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs.

[0163] The oily phase of the emulsions of this invention may be constituted from known

ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise

known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or

an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with

a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a

fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying

wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base

which forms the oily dispersed phase of the cream formulations.

[0164] Emulgents and emulsion stabilizers suitable for use in the formulation of the invention

include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl

mono-stearate and sodium lauryl sulfate. Further emulgents and emulsion stabilizers suitable for

use in the formulation of the invention include Tween® 80.

[0165] The choice of suitable oils or fats for the formulation is based on achieving the desired

cosmetic properties. The cream should preferably be a non-greasy, non-staining and washable

product with suitable consistency to avoid leakage from tubes or other containers. Straight or

branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene

glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl

stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP

may be used, the last three being preferred esters. These may be used alone or in combination

depending on the properties required. Alternatively, high melting point lipids such as white soft

paraffin and/or liquid paraffin or other mineral oils are used.

90o

[0166] Pharmaceutical formulations according to the present invention comprise a

combination according to the invention together with one or more pharmaceutically acceptable

carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations

containing the active ingredient may be in any form suitable for the intended method of

administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil

suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs

may be prepared. Compositions intended for oral use may be prepared according to any method

known to the art for the manufacture of pharmaceutical compositions and such compositions

may contain one or more agents including sweetening agents, flavoring agents, coloring agents

and preserving agents, in order to provide a palatable preparation. Tablets containing the active

ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable

for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents,

such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and

disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch,

gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc.

Tablets may be uncoated or may be coated by known techniques including microencapsulation

to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a

sustained action over a longer period. For example, a time delay material such as glyceryl

monostearate or glyceryl distearate alone or with a wax may be employed.

[0167] Formulations for oral use may be also presented as hard gelatin capsules where the

active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin,

or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium,

such as peanut oil, liquid paraffin or olive oil.

[0168] Aqueous suspensions of the invention contain the active materials in admixture with

excipients suitable for the manufacture of aqueous suspensions. Such excipients include a

on suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).

The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p

hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more

sweetening agents, such as sucrose or saccharin. Further non-limiting examples of suspending

agents include Cyclodextrin and Captisol (=Sulfobutyl ether beta-cyclodextrin; SEB-beta-CD).

[0169] Oil suspensions may be formulated by suspending the active ingredient in a vegetable

oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid

paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin

or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be

added to provide a palatable oral preparation. These compositions may be preserved by the

addition of an antioxidant such as ascorbic acid.

[0170] Dispersible powders and granules of the invention suitable for preparation of an

aqueous suspension by the addition of water provide the active ingredient in admixture with a

dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable

dispersing or wetting agents and suspending agents are exemplified by those disclosed above.

Additional excipients, for example sweetening, flavoring and coloring agents, may also be

present.

[0171] The pharmaceutical compositions of the invention may also be in the form of oil-in

water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a

mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include

naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring

phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and

hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial

esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may

also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with

sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a

demulcent, a preservative, a flavoring or a coloring agent.

[0172] The pharmaceutical compositions of the invention may be in the form of a sterile

injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This

suspension may be formulated according to the known art using those suitable dispersing or

wetting agents and suspending agents which have been mentioned above. The sterile injectable

preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally

acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized

powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's

solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally

be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be

employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid

may likewise be used in the preparation of injectables. Among the acceptable vehicles and

solvents that may be employed are water, Ringer's solution isotonic sodium chloride solution,

and hypertonic sodium chloride solution.

[0173] The amount of active ingredient that may be combined with the carrier material to

produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about

% of the total compositions (weight:weight). The pharmaceutical composition can be

prepared to provide easily measurable amounts for administration. For example, an aqueous

solution intended for intravenous infusion may contain from about 3 to 500 tg of the active

ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about

mL/hr can occur.

[0174] Formulations suitable for topical administration to the eye also include eye drops

wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an

aqueous solvent for the active ingredient. The active ingredient is preferably present in such

formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly

about 1.5% w/w.

[0175] Formulations suitable for topical administration in the mouth include lozenges

comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth;

pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or

sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid

carrier.

[0176] Formulations for rectal administration may be presented as a suppository with a

suitable base comprising for example cocoa butter or a salicylate.

[0177] In some embodiments, the compounds disclosed herein are administered by inhalation.

In some embodiments, formulations suitable for intrapulmonary or nasal administration have a

particle size for example in the range of 0.1 to 500 microns, such as 0.5, 1, 30, 35 etc., which is

administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of 2019-nCoV infections as described below. In some embodiments, the compounds used herein are formulated and dosed as dry powder. In some embodiments, the compounds used herein are formulated and dosed as a nebulized formulation. In some embodiments, the compounds used herein are formulated for delivery by a face mask. In some embodiments, the compounds used herein are formulated for delivery by a face tent.

[0178] Formulations suitable for vaginal administration may be presented as pessaries,

tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active

ingredient such carriers as are known in the art to be appropriate.

[0179] Formulations suitable for parenteral administration include aqueous and non-aqueous

sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes

which render the formulation isotonic with the blood of the intended recipient; and aqueous and

non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0180] The formulations are presented in unit-dose or multi-dose containers, for example

sealed ampoules and vials, and may be stored in a freeze-dried lyophilizedd) condition requiring

only the addition of the sterile liquid carrier, for example water for injection, immediately prior

to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders,

granules and tablets of the kind previously described. Preferred unit dosage formulations are

those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate

fraction thereof, of the active ingredient.

0QA

[0181] It should be understood that in addition to the ingredients particularly mentioned above

the formulations of this invention may include other agents conventional in the art having regard

to the type of formulation in question, for example those suitable for oral administration may

include flavoring agents.

[0182] The invention further provides veterinary compositions comprising at least one active

ingredient as above defined together with a veterinary carrier therefor.

[0183] Veterinary carriers are materials useful for the purpose of administering the

composition and may be solid, liquid or gaseous materials which are otherwise inert or

acceptable in the veterinary art and are compatible with the active ingredient. These veterinary

compositions may be administered orally, parenterally or by any other desired route.

[0184] Compounds of the invention are used to provide controlled release pharmaceutical

formulations containing as active ingredient one or more compounds of the invention

("controlled release formulations") in which the release of the active ingredient are controlled

and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity

profile of a given active ingredient.

4. ROUTES OF ADMINISTRATION

[0185] One or more compounds of the invention (herein referred to as the active ingredients)

are administered by any route appropriate to the condition to be treated. Suitable routes include

oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), vaginal and parenteral

(including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and

the like. It will be appreciated that the preferred route may vary with for example the condition

of the recipient. An advantage of the compounds of this invention is that they are orally

bioavailable and can be dosed orally.

Os

[0186] In some embodiments, the compounds provided herein are administered by inhalation

or by IV infusion. In some embodiments, the compounds provided herein are administered by a

combination of inhalation and IV infusion, for example one or more dose of the compounds

disclosed herein is administered by inhalation and one or more dose is administered by IV

infusion.

[0187] In the methods of the present invention for the treatment of a 2019-nCoV infection, the

compounds of the present invention can be administered at any time to a human who may come

into contact with humans suffering from 2019-nCoV infection or is already suffering from 2019

nCoV infection. In some embodiments, the compounds of the present invention can be

administered prophylactically to humans coming into contact with humans suffering from 2019

nCoV infection or at risk of coming into contact with humans suffering from 2019-nCoV, e.g.

healthcare providers. In some embodiments, administration of the compounds of the present

invention can be to humans testing positive for 2019-nCoV infection but not yet showing

symptoms of 2019-nCoV infection. In some embodiments, administration of the compounds of

the present invention can be to humans upon commencement of symptoms of 2019-nCoV

infection.

[0188] In some embodiments, the methods disclosed herein comprise event driven

administration of the compound of Formula I,II, III, or IV, or a pharmaceutically acceptable salt

thereof, to the subject.

[0189] As used herein, the terms "event driven" or "event driven administration" refer to

thereof, (1) prior to an event (e.g., 2 hours, 1 day, 2 days, 5 day, or 7 or more days prior to the

event) that would expose the individual to 2019-nCoV (or that would otherwise increase the

individual's risk of acquiring 2019-nCoV); and/or (2) during an event (or more than one recurring event) that would expose the individual to 2019-nCoV (or that would otherwise increase the individual's risk of acquiring 2019-nCoV); and/or (3) after an event (or after the final event in a series of recurring events) that would expose the individual to 2019-nCoV (or that would otherwise increase the individual's risk of acquiring 2019-nCoV). In some embodiments, the event driven administration is performed pre-exposure of the subject to the

2019-nCoV. In some embodiments, the event driven administration is performed post-exposure

of the subject to the 2019-nCoV. In some embodiments, the event driven administration is

performed pre-exposure of the subject to the 2019-nCoV and post-exposure of the subject to the

2019-nCoV.

[0190] In certain embodiments, the methods disclosed herein involve administration prior to

and/or after an event that would expose the individual to 2019-nCoV or that would otherwise

increase the individual's risk of acquiring 2019-nCoV, e.g., as pre-exposure prophylaxis (PrEP)

and/or as post-exposure prophylaxis (PEP). In some embodiments, the methods disclosed herein

comprise pre-exposure prophylaxis (PrEP). In some embodiments, methods disclosed herein

comprise post-exposure prophylaxis (PEP).

[0191] In some embodiments, the compound of Formula I,II, III, or IV, or a pharmaceutically

acceptable salt thereof, is administered before exposure of the subject to the 2019-nCoV.

[0192] In some embodiments, the compound of Formula I,II, III, or IV, or a pharmaceutically

acceptable salt thereof, is administered before and after exposure of the subject to the 2019

nCoV.

[0193] In some embodiments, the compound of Formula I,II, III, or IV, or a pharmaceutically

acceptable salt thereof, is administered after exposure of the subject to the 2019-nCoV.

[0194] An example of event driven dosing regimen includes administration of the compound

of Formula I,II, III, or IV, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to 2019-nCoV, followed by administration of the compound of I,II, III, or IV, or a pharmaceutically acceptable salt, every 24 hours during the period of exposure, followed by a further administration of the compound of Formula I,II, III, or IV, or a pharmaceutically acceptable salt thereof, after the last exposure, and one last administration of the compound of

Formula I,II, III, or IV, or a pharmaceutically acceptable salt thereof, 24 hours later.

[0195] A further example of an event driven dosing regimen includes administration of the

compound of Formula I,II, III, or IV, or a pharmaceutically acceptable salt thereof, within 24

hours before 2019-nCoV exposure, then daily administration during the period of exposure,

followed by a last administration approximately 24 hours later after the last exposure (which

may be an increased dose, such as a double dose).

[0196] Effective dose of active ingredient depends at least on the nature of the condition being

treated, toxicity, whether the compound is being used prophylactically or against an active viral

infection, the method of delivery, and the pharmaceutical formulation, and will be determined

by the clinician using conventional dose escalation studies. It can be expected to be from about

0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about 10 mg/kg

body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day;

most typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily

candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to

1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple

doses.

[0197] The effective dose of a compound of the present invention for treating the 2019-nCoV

infection can depend on whether the dose is to be used prophylactically or to treat a human

already suffering from 2019-nCoV infection. Moreover, the dose can depend on whether the

human suffering from 2019-nCoV infection does not yet show symptoms or is already showing symptoms of 2019-nCoV infection. Larger doses may be necessary for treating humans testing positive for 2019-nCoV infection and for humans showing symptoms of 2019-nCoV infection as compared to humans receiving prophylactic treatment.

[0198] Any suitable period of time for administration of the compounds of the present

invention is contemplated. For example, administration can be for from 1 day to 100 days,

including 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 days. The

administration can also be for from 1 week to 15 weeks, including 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,

12, 13, or 14 weeks. Longer periods of administration are also contemplated. The time for

administration can depend on whether the compound is being administered prophylactically or

to treat a human suffering from an 2019-nCoV infection. For example, a prophylactic

administration can be for a period of time while the human is in regular contact with other

humans suffering from an 2019-nCoV infection, and for a suitable period of time following the

last contact with a human suffering from an 2019-nCoV infection. For humans already suffering

from an 2019-nCoV infection, the period of administration can be for any length of time

necessary to treat the patient and a suitable period of time following a negative test for 2019

nCoV infection to ensure the 2019-nCoV infection does not return.

[0199] In some embodiments, the compounds disclosed herein are administered once daily. In

some embodiments, the compounds disclosed herein are administered once every alternate day.

In some embodiments, the compounds disclosed herein are administered once a week. In some

embodiments, the compounds disclosed herein are administered twice a week.

[0200] In some embodiments, the methods described herein comprise administering a loading

dose of one or more compounds disclosed herein on first day, followed by administering a

maintenance dose of the one or more compounds once daily on each subsequent days. The once

daily maintenance dose of the one or more compounds may be administered for as long as required, for example for up to 5 days, up to 7 days, up to 10 days, up to 15 days, up to 20 days, up to 25 days, up to a month or longer. In some embodiments, the once daily maintenance dose is administered for about 6-12 days, for example for about example 8-10 days. In some embodiments, the once daily maintenance dose is administered for about 4 days. In some embodiments, the once daily maintenance dose is administered for about 5 days. In some embodiments, the once daily maintenance dose is administered for about 9 days. In some embodiments, the once daily maintenance dose is administered for about 10 days. The loading dose may be equal to, less than, or greater than the maintenance dose. In some embodiments, the loading dose is greater than the maintenance dose.

[0201] In some embodiments, the methods disclosed herein comprise administering a loading

dose of 150-250 mg on the first day followed by administering a once daily maintenance dose of

about 50-150 mg on the subsequent days. In some embodiments, the once daily maintenance

dose is administered for about 6 to 12 days, for example for about 8-10 days. In some

embodiments, the once daily maintenance dose is administered for about 9 days. In some

embodiments, the once daily maintenance dose is administered for about 2 to 6 days, for

example for about 3-5 days. In some embodiments, the once daily maintenance dose is

administered for about 4 days. In some embodiments, the compound is remdesivir.

[0202] In some embodiments, the methods disclosed herein comprise administering a loading

dose of about 200 mg on the first day followed by administering a once daily maintenance dose

of about 100 mg on subsequent days. In some embodiments, the once daily maintenance dose is

administered for about 6 to 12 days, for example for about 8-10 days. In some embodiments, the

once daily maintenance dose is administered for about 9 days. In some embodiments, the once

daily maintenance dose is administered for about 2 to 6 days, for example for about 3-5 days. In

some embodiments, the once daily maintenance dose is administered for about 4 days. In some

embodiments, the compound is remdesivir.

1 W)

[0203] In some embodiments, the methods disclosed herein comprise administering a loading

dose of about 50-250 mg (e.g. about 100 mg) on the first day followed by administering a once

daily maintenance dose of about 10-100 mg (e.g. about 50 mg) on subsequent days. In some

embodiments, the once daily maintenance dose is administered for about 6 to 12 days, for

example for about 8-10 days. In some embodiments, the once daily maintenance dose is

administered for about 9 days. In some embodiments, the once daily maintenance dose is

administered for about 10 days. In some embodiments, the once daily maintenance dose is

administered for about 2 to 6 days, for example for about 3-5 days. In some embodiments, the

once daily maintenance dose is administered for about 4 days. In some embodiments, the

compound is remdesivir.

[0204] In some embodiments, the loading dose is equal to the maintenance dose, and the

methods disclosed herein comprise administering a dose of one or more compounds disclosed

herein once daily. The once daily dose may be administered for as long as required, for example

forup to5 days,up to7 days,up to 10days,up to 15 days,up to 20days,up to 25 days,up to a

month or longer. In some embodiments, the once daily dose is administered for up to 20 days,

up to 15 days, up to 14 days, up to 13 days, up to 12 days, up to 10 days, up to 8 days, up to 6

days, up to 4 days, up to 3 days, up to 2 days or for one day.

[0205] In some embodiments, the one or more compounds disclosed herein are dosed once

daily, for about 6 to 12 days, for example for about 8-10 days. In some embodiments, the one or

more compounds are administered once daily for about 9 days. In some embodiments, the one or

more compounds are administered once daily for about 10 days. In some embodiments about 50

150 mg of one or more compounds disclosed herein is administered once daily for about 6 to 12

days, for e.g. for about 10 days. In some embodiments about 100 mg of one or more compounds

disclosed herein is administered once daily for about 6 to 12 days, for e.g. for about 10 days. In

some embodiments, the compound is remdesivir.

1 1

[0206] In some embodiments, the one or more compounds disclosed herein are dosed once

daily, for about 1 to 5 days, for example for about 1-3 days. In some embodiments, the one or

more compounds are administered once daily for about 5 days. In some embodiments, the one or

more compounds are administered once daily for about 4 days. In some embodiments, the one or

more compounds are administered once daily for about 3 days. In some embodiments, the one or

more compounds are administered once daily for about 2 days. In some embodiments, the one or

more compounds are administered once daily for about 1 day. In some embodiments about 50

300 mg of one or more compounds disclosed herein is administered once daily for about 3 days,

for e.g. for about 1 day, about 2 days or about 3 days.

5. COMBINATION THERAPY

[0207] The compounds described herein can also be used in combination with one or more

additional therapeutic agents. As such, also provided herein are methods of treatment of the

2019-nCoV virus infection (COVID-19), wherein the methods comprise administering to a

subject in need thereof a compound of the disclosure and a therapeutically effective amount of

one or more additional therapeutic agents.

[0208] In some embodiments, the additional therapeutic agent is an antiviral agent. Any

suitable antiviral agent can be used in the methods described herein. In some embodiments, the

antiviral agent is selected from the group consisting of 5-substituted 2'-deoxyuridine analogues,

nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, non

nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry

inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A

inhibitors, NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulators,

oligonucleotides, antimitotic inhibitors, and combinations thereof.

1 ()

[0209] In some embodiments, the additional therapeutic agent is a 5-substituted 2'

deoxyuridine analogue. For example, in some embodiments, the additional therapeutic agent is

selected from the group consisting of idoxuridine, trifluridine, brivudine [BVDU], and

combinations thereof.

[0210] In some embodiments, the additional therapeutic agent is a nucleoside analogue. For

example, in some embodiments, the additional therapeutic agent is selected from the group

consisting of vidarabine, entecavir (ETV), telbivudine, lamivudine, adefovir dipivoxil, tenofovir

disoproxil fumarate (TDF) and combinations thereof. In some embodiments, the additional

therapeutic agent is favipiravir, ribavirin, galidesivir, or a combination thereof. In some

embodiments, the additional therapeutic agent is -D-N4-hydroxycytidine.

[0211] In some embodiments, the additional therapeutic agent is a pyrophosphate analogue.

For example, in some embodiments, the additional therapeutic agent is foscarnet or

phosphonoacetic acid. In some embodiments, the additional therapeutic agent is foscarnet.

[0212] In some embodiments, the additional therapeutic agent is nucleoside reverse

transcriptase inhibitor. In some embodiments, the antiviral agent is zidovudine, didanosine,

zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof. In some

embodiments, the additional therapeutic agent is sangivamycin, -d-N4-Hydroxycytidine

(NHC), EIDD-2801, EIDD-1931, or a combination thereof. In some embodiments, the antiviral

agent is MK-4482 (EIDD-2801).

[0213] In some embodiments, the additional therapeutic agent is a non-nucleoside reverse

transcriptase inhibitor. In some embodiments, the antiviral agent is selected from the group

consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

[0214] In some embodiments, the additional therapeutic agent is a protease inhibitor. In some

embodiments, the protease inhibitor is a HIV protease inhibitor. For example, in some

1 M embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat, and combinations thereof. In some embodiments, the antiviral agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof. In some embodiments, the protease inhibitor is a HCV NS3/4A protease inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, ribavirin, danoprevir, faldaprevir, vedroprevir, sovaprevir, deldeprevir, narlaprevir and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of voxilaprevir, asunaprevir, boceprevir, paritaprevir, simeprevir, telaprevir, vaniprevir, grazoprevir, and combinations thereof.

[0215] In some embodiments, the additional therapeutic agent is an integrase inhibitor. For

consisting of raltegravir, dolutegravir, elvitegravir, abacavir, lamivudine, and combinations

thereof. In some embodiments, the additional therapeutic agent is selected from the group

consisting of bictegravir, raltegravir, dolutegravir, cabotegravir, elvitegravir, and combinations

consisting of bictegravir, dolutegravir, and cabotegravir, and combinations thereof. In some

embodiments, the additional therapeutic agent is bictegravir.

[0216] In some embodiments, the additional therapeutic agent is an entry inhibitor. For

consisting of docosanol, enfuvirtide, maraviroc, ibalizumab, fostemsavir, leronlimab,

ibalizumab, fostemsavir, leronlimab, palivizumab, respiratory syncytial virus immune globulin,

1(VA intravenous [RSV-IGIV], varicella-zoster immunoglobulin [VariZIG], varicella-zoster immune globulin [VZIG]), and combinations thereof.

[0217] In some embodiments, the additional therapeutic agent is an acyclic guanosine

analogue. For example, in some embodiments, the additional therapeutic agent is selected from

the group consisting of acyclovir, ganciclovir, valacyclovir (also known as valaciclovir),

valganciclovir, penciclovir, famciclovir, and combinations thereof.

[0218] In some embodiments, the additional therapeutic agent is an acyclic nucleoside

phosphonate analogues. For example, in some embodiments, the additional therapeutic agent is

selected from a group consisting of cidofovir, adefovir, adefovir dipivoxil, tenofovir, TDF,

emtricitabine, efavirenz, rilpivirine, elvitegravir, and combinations thereof. In some

embodiment, the additional therapeutic agent is selected from the group consisting of cidofovir,

adefovir, adefovir dipivoxil, tenofovir, TDF, and combinations thereof. In some embodiment,

the additional therapeutic agent is selected from the group consisting of cidofovir, adefovir

dipivoxil, TDF, and combinations thereof.

[0219] In some embodiments, the additional therapeutic agent is a HCV NS5A or NS5B

inhibitor. In some embodiments, the additional therapeutic agent is a NS3/4A protease inhibitor.

In some embodiments, the additional therapeutic agent is a NS5A protein inhibitor. In some

embodiments, the additional therapeutic agent is a NS5B polymerase inhibitor of the

nucleoside/nucleotide type. In some embodiments, the additional therapeutic agent is a NS5B

polymerase inhibitor of the nonnucleoside type. In some embodiments, the additional

therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir,

ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir,

ritonavir, elbasvir, grazoprevir, and combinations thereof. In some embodiments, the additional

1 (VS therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, velpatasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, and combinations thereof.

[0220] In some embodiments, the additional therapeutic agent is an influenza virus inhibitor.

In some embodiments, the additional therapeutic agents is a matrix 2 inhibitor. For example, in

some embodiments, the additional therapeutic agent is selected from the group consisting of

amantadine, rimantadine, and combinations thereof. In some embodiments, the additional

therapeutic agent is a neuraminidase inhibitor. For example, in some embodiments, the

additional therapeutic agent is selected from the group consisting of zanamivir, oseltamivir,

peramivir, laninamivir octanoate, and combinations thereof. In some embodiments, the

additional therapeutic agent is a polymerase inhibitor. For example, in some embodiments, the

additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir, and

combinations thereof. In some embodiments, the additional therapeutic agent is selected from

the group consisting of amantadine, rimantadine, arbidol (umifenovir), baloxavir marboxil,

oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, ribavirin, and

the group consisting of amantadine, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir

octanoate, ribavirin, favipiravir, and combinations thereof. In some embodiments, the additional

therapeutic agent is DAS-181 or XC-221.

[0221] In some embodiments, the additional therapeutic agent is an interferon. In some

embodiments, the additional therapeutic agent is selected from the group consisting of interferon

alfacon 1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfacon 1,

pegylated interferon alfa lb, pegylated interferon alfa 2a (PegIFNa-2a), and PegIFNa-2b. e

alfacon 1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, pegylated interferon alfa 2a

(PegIFNa-2a), and PegIFNa-2b. In some embodiments, the additional therapeutic agent is

1 ()- selected from the group consisting of interferon alfacon 1, pegylated interferon alfa 2a

(PegIFNa-2a), PegIFNa-2b, and ribavirin. In some embodiments, the additional therapeutic

agent is pegylated interferon alfa-2a, pegyated interferon alfa-2b, or a combination thereof. In

some examples, the additional therapeutic agent is interferon-beta. For example, the additional

therapeutic agent is interferon-beta-la, such as SNG-00 L In some embodiments, the additional

therapeutic agent is an interferon--inducing agent, such as tilorone hydrochloride. In some

embodiments, the additional therapeutic agent is IL-17 antagonist such as ixekizumab. In some

embodiments, the additional therapeutic agent is interferon alfa 2 ligand, secukinumab, IMU

838, or vidofludimus.

[0222] In some embodiments, the additional therapeutic agent is an immunostimulatory agent.

In some embodiments, the additional therapeutic agent is an oligonucleotide. In some

embodiments, the additional therapeutic agent is an antimitotic inhibitor. For example, in some

embodiments, the additional therapeutic agent is selected from the group consisting of

fomivirsen, podofilox, imiquimod, sinecatechins, and combinations thereof. In some

embodiments, the additional therapeutic agent is azoximer bromide or IMM-101.

[0223] In some embodiments, the additional therapeutic agent is selected from the group

consisting of besifovir, nitazoxanide, REGN2222, doravirine, sofosbuvir, velpatasvir,

daclatasvir, asunaprevir, beclabuvir, FV100, and letermovir, and combinations thereof.

[0224] In some embodiments, the additional therapeutic agent is an agent for treatment of

RSV. For example, in some embodiments, the antiviral agent is ribavirin, ALS-8112 or

presatovir. For example, in some embodiments, the antiviral agent is ALS-8112 or presatovir.

[0225] In some embodiments, the antiviral agent is DFV890. In some embodiments, the

antiviral agent is MAS825. In some embodiments, the antiviral agent is emetine. In some

embodiments, the antiviral agent is protoporphyrin IX, SnPP protoporphyrin and verteporfin. In some embodiments, the antiviral agent is RBT-9. In some embodiments, the antiviral agent is thymosin. In some embodiments, the additional therapeutic agent is ivennectin.

[0226] In some embodiments, the additional therapeutic agent is an agent for treatment of

picornavirus. In some embodiments, the additional therapeutic agent is selected from the group

consisting of hydantoin, guanidine hydrochloride, L-buthionine sulfoximine, Py-11, and

combinations thereof. In some embodiments, the additional therapeutic agent is a picornavirus

polymerase inhibitor. In some embodiments, the additional therapeutic agent is rupintrivir.

[0227] In some embodiments, the additional therapeutic agent is an agent for treatment of

malaria. For example, the additional therapeutic agent is dihydroartemisinin piperaquine. In

some embodiments, the additional therapeutic agent is pyramax.

[0228] In some embodiments, the additional therapeutic agent is selected from the group

consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone,

proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate,

amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin,

pyrimethamine, MMV-390048, ferroquine, artefenomel mesylate, ganaplacide, DSM-265,

cipargamin, artemisone, and combinations thereof.

[0229] In some embodiments, the additional therapeutic agent is an agent for treatment of

coronavirus. In some embodiments, the additional therapeutic agent is selected from a group

consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, anti

viroporins, and combinations thereof.

[0230] In some embodiments, the additional therapeutic agent is an agent for treatment of

ebola virus. For example, in some embodiments, the additional therapeutic agent is selected

from the group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam©),

MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola

1M9

Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R)-2-(4-amino-5H

pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known

as T-705 or Avigan),T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106

(1-N,7-N-bis[3-(dimethylamino)propyl]-3,9-dimethylquinolino[8,7-h]quinolone-1,7-diamine),

JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo,

brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, FiloVax vaccine,

GOVX-E301, GOVX-E302, ebola virus entry inhibitors (NPC1 inhibitors), rVSV-EBOV, and

combinations thereof. In some embodiments, the additional therapeutic agent is ZMapp,

mAB114, REGEN-EB3, and combinations thereof.

[0231] In some embodiments, the additional therapeutic agent is an agent for treatment of

HCV. In some embodiments, the additional therapeutic agent is a HCV polymerase inhibitor.

For example, in some embodiments, the additional therapeutic agent is selected from the group

consisting of sofosbuvir, GS-6620, PSI-938 , ribavirin, tegobuvir, radalbuvir, MK-0608, and

combinations thereof. In some embodiments, the additional therapeutic agent is a HCV protease

inhibitor. For example, in some embodiments, the additional therapeutic agent is selected from

the group consisting of such as GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

[0232] In some embodiments, the additional therapeutic agent is a NS5A inhibitor. For

consisting of ledipasvir, velpatasvir, and combinations thereof.

[0233] In some embodiments, the additional therapeutic agent is an anti HBV agent. For

example, in some embodiments, the additional therapeutic agent is tenofovir disoproxil fumarate

and emtricitabine, or a combination thereof. Examples of additional anti HBV agents include but

are not limited to alpha-hydroxytropolones, amdoxovir, antroquinonol, beta-hydroxycytosine

nucleosides, , ARB-199, CCC-0975, ccc-R08, elvucitabine, ezetimibe, cyclosporin A,

1fl0 gentiopicrin (gentiopicroside), HH-003, hepalatide, JNJ-56136379, nitazoxanide, birinapant,

NJK14047, NOV-205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131,

levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (Ti Fen Tai), rSIFN-co, PEG-IIFNm, KW

3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1,

HEISCO-106, Hepbarna, IBPB-0061A, Hepuyinfen, DasKloster 0014-01, ISA-204, Jiangantai

(Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613,

TCM-800B, reduced glutathione, RO-6864018, RG-7834, QL-007sofosbuvir, ledipasvir, UB

551, and ZH-2N, and the compounds disclosed in US20150210682, (Roche), US 2016/0122344

(Roche), W02015173164, W02016023877, US2015252057A (Roche), W016128335A1

(Roche), W016120186A1 (Roche), US2016237090A (Roche), W016107833A1 (Roche),

W016107832A1 (Roche), US2016176899A (Roche), W016102438A1 (Roche),

W016012470A1 (Roche), US2016220586A (Roche), and US2015031687A (Roche). In some

embodiments, the additional therapeutic agent is a HBV polymerase inhibitor. Examples of

HBV DNA polymerase inhibitors include, but are not limited to, adefovir (HEPSERA@),

emtricitabine (EMTRIVA@), tenofovir disoproxil fumarate (VIREAD@), tenofovir alafenamide,

tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide

hemifumarate, tenofovir dipivoxil , tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl

ester, CMX-157, tenofovir exalidex, besifovir, entecavir (BARACLUDE@), entecavir maleate,

telbivudine (TYZEKA@), filocilovir, pradefovir, clevudine, ribavirin, lamivudine (EPIVIR

HBV@), phosphazide, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR

11-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate, and HS-10234.

In some embodiments, the additional therapeutic agent is a HBV capsid inhibitor.

[0234] In some embodiments, the additional therapeutic agent is an agent for treatment of

HIV. In some embodiments, the additional therapeutic agent is selected from the group

consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside

1 1M reverse transcriptase inhibitors, HIV nonnucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogues, and combinations thereof.

[0235] In some embodiments, the additional therapeutic agent is selected from the group

consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of

reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV

integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry

inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody

drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases,

homing nucleases, synthetic nucleases, TALENs), and cell therapies (such as chimeric antigen

receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies).

In some embodiments, the additional therapeutic agent is an immunotherapeutic peptides such as

tertomotide. In some embodiments, the additional therapeutic agent is a CCL26 gene inhibitor,

such as mosedipimod.

[0236] In some embodiments, the additional therapeutic agent is selected from the group

consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors,

HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site

(or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors,

latency reversing agents, capsid inhibitors, immune-based therapies, P13K inhibitors, HIV

antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations

thereof. In some embodiments, the additional therapeutic agent is a P13K inhibitor, for example

idelalisib or duvelisib.

[0237] In some examples, the additional therapeutic agent is a HIV combination drug.

Examples of the HIV combination drugs include, but are not limited to

ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine);

BIKTARVY© (bictegravir, emtricitabine, and tenofovir alafenamide); COMPLERA*

(EVIPLERA*; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD©

(elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA*

(tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY@ (tenofovir

alafenamide and emtricitabine); ODEFSEY@ (tenofovir alafenamide, emtricitabine,

and rilpivirine); GENVOYA@ (tenofovir alafenamide, emtricitabine, cobicistat, and

elvitegravir); SYMTUZA* (darunavir, tenofovir alafenamide hemifumarate, emtricitabine,

and cobicistat); SYMFITM (efavirenz, lamivudine, and tenofovir disoproxil

fumarate); CIMDUTM (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine;

tenofovir alafenamide and emtricitabine-; tenofovir

alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate,

emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and

elvitegravir; COMBIVIR© (zidovudine and lamivudine; AZT+3TC);

EPZICOM* (LIVEXA*; abacavir sulfate and lamivudine; ABC+3TC); KALETRA*

(ALUVIA; lopinavir and ritonavir); TRIUMEQ© (dolutegravir, abacavir, and lamivudine);

TRIZIVIR© (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC);

atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir;

darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine

hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and

zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil

fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine + levonorgestrel,

dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine +

emtricitabine + tenofovir disoproxil, lamivudine + abacavir + zidovudine, lamivudine +

abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine,

lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir +

11) zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate

+ emtricitabine + rilpivirine hydrochloride, lopinavir , ritonavir, zidovudine and lamivudine.

[0238] In some embodiments, the additional therapeutic agent is a HIV protease inhibitor. For

example, in some embodiments the additional therapeutic agent is selected from the group

consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir,

fosamprenavir, darunavir, tipranavir, cobicistat, ASC-09, AEBL-2, MK-8718, GS-9500, GS

1156 ,and combinations thereof. For example, in some embodiments the additional therapeutic

agent is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir,

amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, cobicistat. In some

examples, the additional therapeutic agent is selected from the group consisting of amprenavir,

atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir

sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate,

tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, TMC-310911,

and combinations thereof.

[0239] In some embodiments, the additional therapeutic agent is a HIV integrase inhibitor. For

example, in some embodiment, the additional therapeutic agent is selected from the group

consisting of raltegravir, elvitegravir, dolutegravir, abacavir, lamivudine, bictegravir and

combinations thereof. In some embodiment, the additional therapeutic agent is bictegravir. In

some examples, the additional therapeutic agent is selected from a group consisting of

bictegravir, elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric

acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid,

derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid

phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin,

raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long

acting injectable), diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor, ledgins, M-522,

M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172,

NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, VM-3500, cabotegravir, and

combinations thereof.

[0240] In some embodiments, the additional therapeutic agent is a HIV entry inhibitor. For

consisting of enfuvirtide, maraviroc, and combinations thereof. Further examples of HIV entry

inhibitors include, but are not limited to, cenicriviroc, CCR5 inhibitors, gp4l inhibitors, CD4

attachment inhibitors, DS-003 (BMS-599793), gpl20 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab

(PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific

antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu). Examples of

CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0241] In some embodiments, the additional therapeutic agent is a HIV nucleoside reverse

transcriptase inhibitors. In some embodiments, the additional therapeutic agent is a HIV

nonnucleoside reverse transcriptase inhibitors. In some embodiments, the additional therapeutic

agent is an acyclic nucleoside phosphonate analogue. In some embodiments, the additional

therapeutic agent is a HIV capsid inhibitor.

[0242] In some embodiments, the additional therapeutic agent is a HIV nucleoside or

nucleotide inhibitor of reverse transcriptase. For example, the additional therapeutic agent is

selected from the group consisting of adefovir, adefovir dipivoxil, azvudine, emtricitabine,

tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide

hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil

hemifumarate, VIDEX@ and VIDEX EC@ (didanosine, ddl), abacavir, abacavir sulfate,

alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil,

11A

CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine

tidoxil, islatravir, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir

etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, KP-1461, and

combinations thereof.

[0243] In some examples, the additional therapeutic agent is a HIV non-nucleoside or non

nucleotide inhibitor of reverse transcriptase. For example, the additional agent is selected from

the group consisting of dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz,

etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM

023, PC-1005, elsulfavirine rilp (VM-1500), combinations thereof.

[0244] In some embodiments, the additional therapeutic agents are selected from

ATRIPLA* (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA*

(EVIPLERA*; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);

STRIBILD* (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine);

TRUVADA* (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY@

(tenofovir alafenamide and emtricitabine); ODEFSEY@ (tenofovir alafenamide, emtricitabine,

elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir

disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir

alafenamide hemifumarate; TRIUMEQ© (dolutegravir, abacavir, and lamivudine);

dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine;

maraviroc; enfuvirtide; ALUVIA® (KALETRA*; lopinavir and ritonavir); COMBIVIR

(zidovudine and lamivudine; AZT+3TC); EPZICOM* (LIVEXA®; abacavir sulfate and

lamivudine; ABC+3TC); TRIZIVIR© (abacavir sulfate, zidovudine, and lamivudine;

ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat;

atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir;

11 u elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0245] In some embodiments, the additional therapeutic agent is selected from the group

consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide,

aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir,

penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin,

perampanel, eszopiclone, and zopiclone.

[0246] In some embodiments, the additional therapeutic agent is an inhibitor of Bruton

tyrosine kinase (BTK, AGMX1, AT, ATK, BPK, IGHD3, IMD1, PSCTK1, XLA; NCBI Gene

ID: 695). For example, in some embodiments, the additional therapeutic agent is selected from

the group consisting of (S)-6-amino-9-(1-(but-2-ynoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl)

7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, CB988, HM71224, ibrutinib

(Imbruvica), M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib

(CC-292), TAK-020, vecabrutinib, ARQ-531, SHR-1459, DTRMWXHS-12, TAS-5315,

AZD6738, calquence, danvatirsen, and combinations thereof. In some embodiments, the

additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib,

acalabrutinib, and combinations thereof. In some embodiments, the additional therapeutic agent

is selected from a group consisting of tirabrutinib, ibrutinib, and combinations thereof. In some

embodiments, the additional therapeutic agent is a receptor tyrosine kinase inhibitor (RTKI). In

some embodiments, the additional therapeutic agent is tyrphostin A9 (A9). In some

1 16 embodiments, the additional therapeutic agent is a TEK receptor tyrosine kinase inhibitor. In some embodiments, the additional therapeutic agent is abivertinib maleate (STI-5656). In some embodiments, the additional therapeutic agent is a tyrosine kinase inhibitor, such as masitinib.

[0247] In some embodiments, the additional therapeutic agent is a sphingosine kinase-2 (sk2)

inhibitor, such as opaganib. In some embodiments, the additional therapeutic agent is a kinase

inhibitor such as pacritinib. In some embodiments, the additional therapeutic agent is an Axl

tyrosine kinase receptor inhibitor, such as bemcentinib. In some embodiments, the additional

therapeutic agent is a FYVE finger phosphoinositide kinase inhibitor. In some embodiments, the

additional therapeutic agent is a checkpoint kinase inhibitor, such as prexasertib. In some

embodiments, the additional therapeutic agent is a MAP kinase inhibitor, such as KTH-222,

ATI-450. In some embodiments, the additional therapeutic agent is a mTOR inhibitor, such as

sirolimus. In some embodiments, the additional therapeutic agent is a pi3k/ mTOR inhibitor

such as dactolisib. In some embodiments, the additional therapeutic agent is a Hsp90 inhibitor,

such as ganetespib, ADX-1612. In some embodiments, the additional therapeutic agent is a

MEK inhibitor such as ATR-002. In some embodiments, the additional therapeutic agent is a

topoisomerase II inhibitor, such as etoposide. In some embodiments, the additional therapeutic

agent is an exportin 1 inhibitor, such as selinexor, verdinexor. In some embodiments, the

additional therapeutic agent is a dual inhibitor of PARP1/2 and Tankyrase 1/2, such as 2X-121.

In some embodiments, the additional therapeutic agent is a cyclin dependent kinase inhibitor,

such as CYC-065, CYC-202. In some embodiments, the additional therapeutic agent is a

cytosine DNA methyltransferase inhibitor, such as decitabine. In some embodiments, the

additional therapeutic agent is a DHFR inhibitor, such as methotrexate. In some embodiments,

the additional therapeutic agent is a small ubiquitin related modifier inhibitor, such as TAK-981.

In some embodiments, the additional therapeutic agent is an integrin agonist such as 7HP-349.

In some embodiments, the additional therapeutic agent is a BET inhibitor, such as apabetalone.

S11'7

In some embodiments, the additional therapeutic agent is a BRD4 inhibitor, such as CPI-0610,

ABBV-744. In some embodiments, the additional therapeutic agent is a ER1 inhibitor, such as

toremifene.

[0248] In some embodiments, the additional therapeutic agent is a KRAS inhibitor. For

consisting of AMG-510, COTI-219, MRTX-1257, ARS-3248, ARS-853, WDB-178, BI-3406,

BI-1701963, ARS-1620 (G12C), SML-8-73-1 (G12C), Compound 3144 (G12D),

Kobe0065/2602 (Ras GTP), RT11, MRTX-849 (G12C) and K-Ras(G12D)-selective inhibitory

peptides, including KRpep-2 (Ac-RRCPLYISYDPVCRR-NH2), KRpep-2d (Ac

RRRRCPLYISYDPVCRRRR-NH2), and combinations thereof.

[0249] In some embodiments, the additional therapeutic agent is an alkylating agent, such as

melphalan.

[0250] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. For

example, in some embodiments, the additional therapeutic agent is selected from a group

consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof. in some

embodiments, the additional therapeutic agent is carfilzomib.

[0251] In some embodiments, the additional therapeutic agent is a vaccine. For example, in

some embodiments, the additional therapeutic agent is a DNA vaccine, RNA vaccine, live

attenuated vaccine, therapeutic vaccine, prophylactic vaccine, protein based vaccine, or a

combination thereof. In some embodiments, the additional therapeutic agent is mRNA-1273. In

some embodiments, the additional therapeutic agent is INO-4800 or INO-4700. In some

embodiments, the additional therapeutic agent is live-attenuated RSV vaccine MEDI-559,

human monoclonal antibody REGN2222 against RSV, palivizumab, respiratory syncytial virus

immune globulin, intravenous [RSV-IGIV], and combinations thereof. In some embodiments,

119R the additional therapeutic agent is a HBV vaccine, for example pediarix, engerix-B, and recombivax HB. In some embodiments, the additional therapeutic agent is a VZV vaccine, for example zostavax and varivax. In some embodiments, the additional therapeutic agent is a HPV vaccine, for example cervarix, gardasil 9, and gardasil. In some embodiments, the additional therapeutic agent is an influenza virus vaccine. For example, a (i) monovalent vaccine for influenza A (e.g. influenza A [H5N1] virus monovalent vaccine and influenza A [H1N1] 2009 virus monovalent vaccines), (ii) trivalent vaccine for influenza A and B viruses (e.g. Afluria,

Agriflu, Fluad, Fluarix, Flublok, Flucelvax, FluLaval, Fluvirin, and Fluzone), and (iii)

quadrivalent vaccine for influenza A and B viruses (FluMist, Fluarix, Fluzone, and FluLaval). In

some embodiments, the additional therapeutic agent is a human adenovirus vaccine (e.g.

Adenovirus Type 4 and Type 7 Vaccine, Live, Oral). In some embodiments, the additional

therapeutic agent is a rotavirus vaccine (e.g. Rotarix for rotavirus serotype G, G3, G4, or G9

and RotaTeq for rotavirus serotype Gi, G2, G3, or G4). In some embodiments, the additional

therapeutic agent is a hepatitis A virus vaccine (e.g. Havrix and Vaqta). In some embodiments,

the additional therapeutic agent is poliovirus vaccines (e.g. Kinrix, Quadracel, and Ipol). In

some embodiments, the additional therapeutic agent is a yellow fever virus vaccine (e.g. YF

Vax). In some embodiments, the additional therapeutic agent is a Japanese encephalitis virus

vaccines (e.g. Ixiaro and JE-Vax). In some embodiments, the additional therapeutic agent is a

measles vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional therapeutic

agent is a mumps vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the additional

therapeutic agent is a rubella vaccine (e.g. M-M-R II and ProQuad). In some embodiments, the

additional therapeutic agent is a varicella vaccine (e.g. ProQuad). In some embodiments, the

additional therapeutic agent is a rabies vaccine (e.g. Imovax and RabAvert). In some

embodiments, the additional therapeutic agent is a variola virus (smallpox) vaccine

(ACAM2000). In some embodiments, the additional therapeutic agent is a and hepatitis E virus

1 10

(HEV) vaccine (e.g. HEV239). In some embodiments, the additional therapeutic agent is a 2019

nCov vaccine. In some embodiments, the additional therapeutic agent is Ad5-nCoV. In some

embodiments, the additional therapeutic agents in the mRNA vaccine BNT-162. In some

embodiments, the additional therapeutic agent is a BCG vaccine. In some embodiments, the

additional therapeutic agent is Pfizer-BioNTech COVID-19 vaccine. In some embodiments, the

additional therapeutic agent is Moderna Covid-19 vaccine. In some embodiments, the additional

therapeutic agent is AZD1222 (astrazeneca Covid-19 vaccine). In some embodiments, the

additional therapeutic agent is a poliovirus vaccine, e.g. OPV.

[0252] In some embodiments, the additional therapeutic agent is BNT162al, BNT162bl,

BNT162b2, or BNT162c2 (prime/boost, single or multiple doses). In some embodiments, the

additional agent is AZD1222 (ChAdOx1 nCov-19) vaccine. In some embodiments, the

additional agent is Gam-COVID-Vac (Ad26), Gam-COVID-Vac (Ad5), Gam-COVID-Vac

(Ad26 Prime-boost), Covax-19, or NasoVAX. In some embodiments, the additional therapeutic

agents is LUNAR-COV19 (ARCT-021). In some embodiments, the additional agent is

TerraCoV2. In some embodiments, the additional agent is COVID-19 S-Trimer. In some

embodiments, the additional agent is TNX-1810, TNX-1820, or TNX-1830. In some

embodiments, the additional agent is VaxiPatch COVID-19 vaccine. In some embodiments, the

additional agent is VBI-2901. In some embodiments, the additional agent is VLA-2001. In

some embodiments, the additional agent is exoVACC-SARS-CoV2CoV-2. In some

embodiments, the additional agent is SCB-2019. In some embodiments, the additional agent is

MV-SARS-CoV-2. In some embodiments, the additional agent is NVX-CoV2373, Matrix-M or

NVX-CoV2373. In some embodiments, the additional agent is BBV152A, B, C, PicoVacc,

KBP-COVID-19, MF59 adjuvanted SARS-CoV-2 Sclamp, MVC-COV1901, SCB-2019

(COVID-19 S-Trimer + CpG1O18+ASO3), TMV-083, V-591, VPM1002, or V-SARS.

1 2)

[0253] In some embodiments, the additional therapeutic agent is an antibody, for example a

monoclonal antibody. For example, the additional therapeutic agent is an antibody against 2019

nCov selected from the group consisting of the Regeneron antibodies, the Wuxi Antibodies, the

Vir Biotechnology Antibodies, antibodies that target the SARS-CoV-2 spike protein, antibodies

that can neutralize SARS-CoV-2 (SARS-CoV-2 neutralizing antibodies), and combinations

thereof. In some embodiments, the additional therapeutic agent is anti-SARS CoV antibody CR

3022. In some embodiments, the additional therapeutic agent is aPD-1 antibody. In some

embodiments, the additional therapeutic agent is anti-IL-6R mAb. For example, the additional

therapeutic agent is TZLS-501 or siltuximab. In some embodiments, the additional therapeutic

agent is an antibody that targets specific sites on ACE2. In some embodiments, the additional

therapeutic agent is a polypeptide targeting SARS-CoV-2 spike protein (S-protein). In some

embodiments, the additional therapeutic agent is a virus suppressing factor (VSF, HzVSFv13).

[0254] In some embodiments, the additional therapeutic agent is an anti-CD147 antibody. For

example, the additional therapeutic agent is meplazumab.

[0255] In some embodiments, the additional therapeutic agent is a phosphodiesterase type 4

(PDE4) or phosphodiesterase type 5 (PDE5) inhibitor. In some embodiments, the additional

therapeutic agent is a PDE5 inhibitor, for example, the additional therapeutic agent is sildenafil.

In some embodiments, the additional therapeutic agent is a PDE4 inhibitor, for example, the

additional therapeutic agent is brilacidin.

[0256] In some embodiments, the additional therapeutic agent is an agent targeting NKGA2.

In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some

embodiments, the additional therapeutic agent is NKG2 A B activating NK receptor antagonist,

such as monalizumab. In some examples, the additional therapeutic agent is a CTLA-4

checkpoint inhibitor, such as BPI-002.

[0257] In some embodiments, the additional therapeutic agent is a CD73 antagonist, such as

CPI-006.

[0258] In some embodiments, the additional therapeutic agent is recombinant cytokine gene

derived protein injection.

[0259] In some embodiments, the additional therapeutic agent is a polymerase inhibitor. In

some embodiments, the additional therapeutic agent is a DNA polymerase inhibitor. For

example, in some embodiments, the additional therapeutic agent is cidofovir. In some

embodiments, the additional therapeutic agent is lamivudine. In some embodiments, the

additional therapeutic agent is a RNA polymerase inhibitor. For example, in some embodiments,

the additional therapeutic agent is selected from the group consisting of ribavirin, favipiravir,

lamivudine, pimodivir and combination thereof. In some embodiments, the additional

therapeutic agent is selected from the group consisting of ribavirin, favipiravir, pimodivir and

combinations thereof.

[0260] In some embodiments, the additional therapeutic agent is selected from the group

consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine,

darunavir and cobicistat, abidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir

alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

[0261] In some embodiments, the additional therapeutic agent is a beta-catenin inhibitor. For

example, the additional therapeutic agent is tetrandrine.

[0262] In some embodiments, the additional therapeutic agent is a trypsin inhibitor, for

example the additional therapeutic agent is ulinastatin. In some embodiments, the additional

therapeutic agent is TAK-671.

[0263] In some embodiments, the additional therapeutic agent is selected from the group

consisting of ABBV-744, dBET6, MZ1, CPI-0610, Sapanisertib, Rapamycin, Zotatifin,

Verdinexor, Chloroquine, Dabrafenib, WDB002, Sanglifehrin A, FK-506, Pevonedistat,

Ternatin 4, 4E2RCat, Tomivosertib, PS3061, IHVR-19029, Captopril, Lisinopril, Camostat,

Nafamostat, Chloramphenicol, Tigecycline, Linezolid, and combinations thereof.

[0264] In some embodiments, the additional therapeutic agent is selected form the group

consisting of JQ-1, RVX-208,silmitasertib, TMCB, apicidin, valproic acid, Bafilomycin Al, E

52862, PD-144418, RS-PPCC, PD28, haloperidol, entacapone, indomethacin, Metformin,

Ponatinib, H-89, Merimepodib, Migalastat, Mycophenolic acid, Ribavirin, XL413, CCT 365623,

Midostaurin, Ruxolitinib, ZINC1775962367, ZINC4326719, ZINC4511851, ZINC95559591,

AC-55541,AZ8838,Daunorubicin,GB110, S-verapamil, AZ3451, and combinations thereof.

[0265] In some embodiments, the additional therapeutic agent is selected form a group

consisting of tilorone, cyclosporine, loperamide, mefloquine, amodiaquine, proscillaridin,

digitoxin, digoxin, hexachlorophene, hydroxyprogesterone caproate, salinomycin, ouabain,

cepharanthine, ciclesonide, oxyclozanide, anidulafungin, gilteritinib, berbamine, tetrandrine,

abemaciclib, ivacaftor, bazedoxifene, niclosamide, eltrombopag, and combinations thereof.

[0266] In some embodiments, the additional therapeutic agent is a drug targeting the

coronavirus main protease 3CLpro (e.g. lopinavir). In some embodiments the additional

therapeutic agent is a drug targeting the papain-like protease PLpro (e.g. lopinavir). In some

examples, the additional therapeutic agent is a drug that functions as a virus-host cell fusion

inhibitor to prevent viral entry into host cells (e.g. arbidol). In some embodiments, the additional

therapeutic agent is a TMPRSS2 inhibitor (e.g. camostat mesylate).

[0267] In some embodiments, the additional therapeutic agent is a serine protease inhibitor, such

as LB1148, upamostat, RHB-107, or alpha-1 antitrypsin.

[0268] In some embodiments, the additional therapeutic agent is an inhibitor of neutrophil elastase, such as lonodelestat.

[0269] In some embodiments, the additional therapeutic agent is an a-ketoamide.

[0270] In some examples, the additional therapeutic agent is a poly-ADP-ribose polymerase 1

(PARP1) inhibitor, for example, the additional therapeutic agent is CVL218.

[0271] In some embodiments, the additional therapeutic agent is selected from the group

consisting of 6'-fluorinated aristeromycin analogues, acyclovir fleximer analogues, disulfiram,

thiopurine analogues, ASC09F, GC376, GC813, phenylisoserine derivatives, neuroiminidase

inhibitor analogues, pyrithiobac derivatives, bananins and 5-hydroxychromone derivatives,

SSYA10-001, griffithsin, HR2P-M1, HR2P-M2, P21S10, Dihydrotanshinone E-64-C and E-64

D, OC43-HR2P, MERS-5HB, 229E-HR1P, 229E-HR2P, resveratrol, 1-thia-4-azaspiro[4.5]

decan-3-one derivatives, gemcitabine hydrochloride, loperamide, recombinant interferons,

cyclosporine A, alisporivir, imatinib mesylate, dasatinib, selumetinib, trametinib, rapamycin,

saracatinib, chlorpromazine, triflupromazine, fluphenazine, thiethylperazine, promethazine,

cyclophilin inhibitors, K11777, camostat, k22, teicoplanin derivatives, benzo-heterocyclic amine

derivatives N30, mycophenolic acid, silvestrol, and combinations thereof.

[0272] In some embodiments, the additional therapeutic agent is an antibody. In some

embodiments, the additional therapeutic agent is an antibody that binds to a coronavirus, for

example an antibody that binds to SARS or MERS. In some embodiments, the additional

therapeutic agent is a of 2019-nCoV virus antibody.

[0273] In some embodiments, the additional therapeutic agent is LY-CoV555. In some

embodiments, the additional therapeutic agent is S309. In some embodiments, the additional

therapeutic agent is SAB-185. In some embodiments, the additional therapeutic agent is CB6. In

some embodiments, the additional therapeutic agent is STI-1499. In some embodiments, the

1'M additional therapeutic agent is JS016. In some embodiments, the additional therapeutic agent is

VNAR. In some embodiments, the additional therapeutic agent is VIR-7832 and/or VIR-7831.

In some embodiments, the additional therapeutic agent is REGN-COV2 (REGN10933

+ RGN10987) In some embodiments, the additional therapeutic agent is BAT2020, BAT2019. In

some embodiments, the additional therapeutic agent is 47D11. In some embodiments, the

additional therapeutic agent is COVI-SHIELD. In some embodiments, the additional therapeutic

agent is BRII-196, BRII-198. In some embodiments, the additional therapeutic agent is INM

005, SCTA01, TY-027, XAV-19.

[0274] Compositions of the invention are also used in combination with other active

ingredients. For the treatment of 2019-nCoV virus infections, preferably, the other active

therapeutic agent is active against coronavirus infections, for example 2019-nCoV virus

infections. The compounds and compositions of the present invention are also intended for use

with general care provided patients with 2019-nCoV viral infections, including parenteral fluids

(including dextrose saline and Ringer's lactate) and nutrition, antibiotic (including

metronidazole and cephalosporin antibiotics, such as ceftriaxone and cefuroxime) and/or

antifungal prophylaxis, fever and pain medication, antiemetic (such as metoclopramide) and/or

antidiarrheal agents, vitamin and mineral supplements (including Vitamin K and zinc sulfate),

anti-inflammatory agents ( such as ibuprofen or steroids), corticosteroids such as

methylprednisolone, immonumodulatory medications (eg interferon), other small molecule or

biologics antiviral agents targeting 2019-nCoV (such as but not limited to lopinavir/ritonavir,

EIDD-1931, favipiravir, ribavirine, neutralizing antibodies, etc), vaccines, pain medications, and

medications for other common diseases in the patient population, such anti-malarial agents

(including artemether and artesunate-lumefantrine combination therapy), typhoid (including

quinolone antibiotics, such as ciprofloxacin, macrolide antibiotics, such as azithromycin,

cephalosporin antibiotics, such as ceftriaxone, or aminopenicillins, such as ampicillin), or

1 1S shigellosis. In some embodiments, the additional therapeutic agent is dihydroartemisinin/piperaquine. In some embodiments, the additional therapeutic agent is a corticosteroid, for example the additional therapeutic agent is ciclesonide. In some embodiments, the compounds disclosed herein are used in combination with amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, cholecalciferol, vitamin C, prednisone, mometasone, or budenoside.

[0275] In some embodiments, the compounds disclosed herein are used in combination with

inhibitors such as Panaphix (PAX-1), which inhibit production of pro-inflammatory cytokines.

In some embodiments, the compounds disclosed herein are used in combination with inhibitors

such as NCP-112 which inhibit excessive immune response such as cytokine storm.

[0276] In some embodiments, the additional therapeutic agent is an antifungal agent, for

example itraconazole or 17-OH- itraconazole.

[0277] In some examples, the additional therapeutic agent is an immunomodulator. Examples

of immune-based therapies include toll-like receptors modulators such as tirl, tlr2, tlr3, tr4, tr5,

tlr6, tlr7, tlr8, tlr9, trirO, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1)

modulators; programmed death-ligand 1 (Pd-Li) modulators; IL-15 modulators; DermaVir;

interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa;

interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea;

mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin;

polymer polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559;

CYT-107, interleukin-15/Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR

262, NKTR-214, normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinant

interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2

modulators, SB-9200, and IR-103. In some embodiments, the additional therapeutic agent is

1 IA fingolimod, leflunomide, or a combination thereof. In some embodiments, the additional therapeutic agent is thalidomide. In some embodiments, the additional therapeutic agent is

CD24Fc. In some embodiments, the additional therapeutic agent is a type I IL-1 receptor

antagonists, such as anakinra. In some embodiments, the additional therapeutic agent is a TLR4

antagonist, such as EB-05.

[0278] In some embodiments, the additional therapeutic agent is nivolumab, efineptakin alfa,

lactoferrin, ozanimod, astegolimab (MSTT1041A, RG-6149), or UTTR1147A. In some

embodiments, the additional therapeutic agent is Ampligen. In some embodiments, the

additional therapeutic agent is lefitolimod. In some embodiments, the additional therapeutic

agent is RPH-104. In some embodiments, the additional therapeutic agent is canakinumab. In

some embodiments, the additional therapeutic agent is an IL-33 ligand inhibitor such as

MED13506. In some embodiments, the additional therapeutic agent is an IL-5 receptor

antagonist, such as mepolizumab. In some embodiments, the additional therapeutic agent is an

IL-12 inhibitor, such as apilimod. In some embodiments, the additional therapeutic agent is a IL

receptor agonist, such as N-803.

[0279] In some embodiments, the additional therapeutic agent is an interferon gamma ligand

inhibitor, such as emapalumab.

[0280] In some embodiments, the additional therapeutic agent is an IL-6 inhibitor, for example

tocilizumab, sarilumab, or a combination thereof. In some embodiments, the additional

therapeutic agent is tocilizumab. In some embodiments, the additional therapeutic agent is an IL

6 inhibitor, for example tocilizumab, sarilumab, olokizumab, sirukumab, clazakizumab,

levilimab or a combination thereof.

1 97

[0281] In some embodiments, the additional therapeutic agent is a nicotinamide

phosphoribosyltransferase inhibitors. For example, the additional therapeutic agent is

enamptcumab.

[0282] In some embodiments, the additional therapeutic agent is a dipeptidase 1 (DPEP-1)

inhibitor. For example, the additional therapeutic agent is Metablok (LSALT peptide).

[0283] In some embodiments, the additional therapeutic agent is an anti-TNF inhibitor. For

example, the additional therapeutic agent is adalimumab, etanercept, golinunab, inflixinab, or

a combination thereof. In some embodiments, the additional therapeutic agent is a TNF alpha

ligand inhibitor, such as XProl595.

[0284] In some embodiments, the additional therapeutic agent is a JAK inhibitor, for example

the additional therapeutic agent is baricitinib, filgotinib, olumiant, or a combination thereof. In

some examples, the additional therapeutic agent is jaktinib. In some embodiments, the additional

therapeutic agent is tofacitinib or TD-0903.

[0285] In some embodiments, the additional therapeutic agent is an inflammation inhibitor, for

example pirfenidone. In some embodiments, the additional therapeutic agent is LYT-100.

[0286] In some embodiments, the additional therapeutic agent is an anti-inflammatory agent,

such as dociparstat sodium. In some embodiments, the additional agent is used in the treatment

of septic shock, such as nangibotide. In some embodiments, the additional therapeutic agent is a

CCR1 antagonist, such as MLN-3897. In some embodiments, the additional therapeutic agent

targets IKKj and NFw, such as OP-101. In some embodiment, the additional therapeutic agent

is a glucocorticoid receptor agonist, such as hydrocortisone or dexamethasone. In some

embodiments, the additional therapeutic agent is an immunosuppressant, such as tacrolimus,

BXT-10, ibudilast, FP-025, apremilast, abatacept, crizanlizumab, itolizumab, bardoxolone

methyl, M-5049. In some embodiments, the additional therapeutic agent is a RIP-1 kinase

119Z inhibitor, such as DNL-758. In some embodiments, the additional therapeutic agent is a IL-8 receptor antagonist, such as BMS-986253 (HuMax-IL8). In some embodiments, the additional therapeutic agent is a CD14 inhibitor, such as IC-14. In some embodiments, the additional therapeutic agent is a Dihydroorotate dehydrogenase (DHODH) inhibitor, such as brequinar,

PCT-299. In some embodiments, the additional therapeutic is anti-fibrotic, such as RT-1840,

nintedanib, GB-0139, nintedanib, pamrevlumab. In some embodiments, the additional

therapeutic is a hepatocyte growth factor (HGF) mimetic, such as SNV-003 (ANG-3777).

[0287] In some embodiments, the additional therapeutic agent is an A3 adenosine receptor

(A3AR) antagonist, for example the additional therapeutic agent is piclidenoson.

[0288] In some embodiments, the additional therapeutic agent is an antibiotic for secondary

bacterial pneumonia. For example, the additional therapeutic agent is macrolide antibiotics (e.g.

azithromycin, clarithromycin, and mycoplasma pneumoniae), fluoroquinolones (e.g.

ciprofloxacin and levofloxacin), tetracyclines (e.g. doxycycline and tetracycline), or a

combination thereof. In some embodiments, the additional therapeutic agent is XEL 1004. In

some embodiments, the additional therapeutic agent is eravacycline.

[0289] In some embodiments, the compounds disclosed herein are used in combination with

pneumonia standard of care (see e.g. Pediatric Community Pneumonia Guidelines, CID 2011:53

(1 October)). Treatment for pneumonia generally involves curing the infection and preventing

complications. Specific treatment will depend on several factors, including the type and severity

of pneumonia, age and overall health of the individuals. The options include: (i) antibiotics, (ii)

cough medicine, and (iii) fever reducers/pain relievers (for e.g. aspirin, ibuprofen (Advil, Motrin

IB, others) and acetaminophen (Tylenol, others)). In some embodiments, the additional

therapeutic agent is bromhexine anti-cough.

[0290] In some embodiments, the compounds disclosed herein are used in combination with

immunoglobulin from cured COVID-19 patients. In some embodiments, the compounds

disclosed herein are used in combination with plasma transfusion. In some examples, the

compounds disclosed herein are used in combination with TAK-888 (anti-SARS-CoV-2

polyclonal hyperimmune globulin (H-IG)). In some embodiments, the compounds disclosed

herein are used in combination with COVID-19 convalescent plasma or immunoglobulin. In

some embodiments, the compounds described herein are used in combination with COVID-EIG

or COVID-HIG. In some embodiments, the compounds disclosed herein are used in

combination with stem cells. For example, in some embodiments, the compounds disclosed

herein are used in combination with MultiStem or Remestemcel-L (mesenchymal stem cells). In

some embodiments, the compounds described herein are used in combination with allogenic

mesenchymal-like cells, for example in combination with PLX cells. In some embodiments, the

compounds described herein are used in combination with allogenic cell therapy, for example in

combination with CK-0802. In some embodiments, the compounds described herein are used in

combination with Pluristem or ACT-20.

[0291] In some examples, the additional therapeutic agent is an TLR agonist. Examples of

TLR agonists include, but are not limited to, vesatolimod (GS-9620), GS-986, IR-103,

lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008,

motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG

7854, telratolimod.RO-7020531. In some embodiments the additional therapeutic agent is PUL

042. In some embodiments, the additional therapeutic agent is polyinosinic-polycytidylic acid

(poly I:C).

[0292] In some examples, the additional therapeutic agent is selected from the group

consisting of bortezomid, flurazepam, ponatinib, sorafenib, paramethasone, clocortolone,

flucloxacillin, sertindole, clevidipine, atorvastatin, cinolazepam, clofazimine, fosaprepitant, and

11() combinations thereof. In some examples, the additional therapeutic agent is simvastatin or rosuvastatin.

[0293] In some examples, the additional therapeutic agent is carrimycin, suramin, triazavirin,

dipyridamole, bevacizumab, meplazumab, GD31 (rhizobium), NLRP inflammasome inhibitor,

or a-ketoamine. In some embodiments, the additional therapeutic agent is recombinant human

angiotensin-converting enzyme 2 (rhACE2). In some embodiments, the additional therapeutic

agent is viral macrophage inflammatory protein (vMIP).

[0294] In some embodiments, the additional therapeutic agent is a recombinant human

angiotensin-converting enzyme 2 (rhACE2), for example APN-01. In some embodiments, the

additional therapeutic agent is an angiotensin II receptor agonist. In some examples, the

additional therapeutic agent is a partial agonist of AT2 or a partial antagonist of AT1. In some

embodiments, the additional therapeutic agent is L-163491. In some embodiments, the

additional therapeutic agent is ACE2-Fc fusion protein, for example the additional therapeutic

agent is STI-4398. . In some embodiments, the additional therapeutic agent is valsartan,

losartan, candesartan, eprosartan, irbesartan, olmesartan. In some embodiments, the additional

therapeutic agent is VP-01, TXA-127. In some embodiments, the additional therapeutic agent is

telmisartan.

[0295] In some embodiments, the additional therapeutic agent is an ACE inhibitor, such as

ramipril, captopril, enalapril, or lisonopril. In some embodiments, the additional therapeutic

agent is an aldose reductase inhibitor, such as AT-001.

[0296] In some embodiments, the additional therapeutic agent is a platelet inhibitor. For

example, the additional therapeutic agent is dipyridamole.

[0297] In some embodiments, the additional therapeutic agent is an anti-coagulant, such as

heparins (heparin and low molecular weight heparin), aspirin, apixaban, dabigatran, edoxaban, argatroban, enoxaparin, fondaparinux. In some embodiments, the additional therapeutic agent is a tissue factor inhibitor, such as AB-201. In some embodiments, the additional therapeutic is a

Factor XIIa antagonist, such as garadacimab. In some embodiments, the additional therapeutic

agent is a VE-PTP inhibitor, such as razuprotafib. In some embodiments, the additional

therapeutic agent is a VIP 2 receptor agonist, such as PB-1046. In some embodiments, the

additional therapeutic agent is an anti-thrombotic, such as defibrotide, rivaroxaban, alteplase,

tirofiban, clopidogrel, prasugrel, bemiparin, bivalirudin, sulodexide, tranexamic acid. In some

embodiments, the additional therapeutic agent is a vasodilator, such as iloprost, ventaprost,

vazegepant, angiotensin 1-7, ambrisentan, NORS, pentoxifylline, propranolol, RESP301,

sodium nitrite, TRV-027. In some embodiments, the additional therapeutic agent is a blood

clotting modulator, such as lanadelumab. In some embodiments, the additional therapeutic agent

is a diuretic, such as an aldosterone antagonist, such as spironolactone. In some embodiments,

the additional therapeutic agent is antihypoxic, such as trans-sodium crocetinate. In some

embodiments, the additional therapeutic agent is MK-5475.

[0298] In some embodiments, the additional therapeutic agent is a hypoxia-inducible factor

(HF) prolyl hydroxylase-2 (PHD-2) inhibitor such as desidustat or vadadustat. In some

embodiments, the additional therapeutic agent is a renin inhibitor, such as aliskiren. In some

embodiments, the additional therapeutic agent is a calcium channel inhibitor such as nifedipine.

In some embodiments, the additional therapeutic agent is a chelating agent, such as desferal,

deferiprone, deferoxamine. In some embodiments, the additional therapeutic agent is a retinoic

acid receptor agonist, such as isotretinoin or fenretinide. In some embodiments, the additional

therapeutic agent is an AMPA receptor modulator, such as traneurocin. In some embodiments,

the additional therapeutic agent is a human antimicrobial peptide, such as LL-37i. In some

embodiments, the additional therapeutic agent is a microbiome modulator, such as EDP-1815,

KB-109. In some embodiments, the additional therapeutic agent is an estrogen receptor

12') antagonist, such as tamoxifen. In some embodiments, the additional therapeutic agent is an androgen receptor antagonist such as bicalutamide, enzalutamide.

[0299] In some embodiments, the additional therapeutic agent is a GNRH receptor antagonist,

such as degarelix. In some embodiments, the additional therapeutic agent is a sex hormone

modulator, such as dutasteride. In some embodiments, the additional therapeutic agent is a

calpain inhibitor, such as BLD-2660. In some embodiments, the additional therapeutic agent is a

GM-CSF ligand inhibitor such as gimsilumab, lenzilumab, namilumab, TJM2 or otilimab. In

some embodiments, the additional therapeutic agent is a GM-CSF receptor antagonist, such as

mavrilimumab. In some embodiments, the additional therapeutic agent is a GM-CSF receptor

agonist, such as sargramostim. In some embodiments, the additional therapeutic agent is an

alpha 1 adrenoreceptor antagonist such as prazosin. In some embodiments, the additional

therapeutic agent is a neuropilin 2 inhibitor, such as ATYR-1923. In some embodiments, the

additional therapeutic agent is an activated calcium (CRAC) channel inhibitor, such as CM

4620. In some embodiments, the additional therapeutic agent is a proto-oncogene Mas agonist,

such as BI0101. In some embodiments, the additional therapeutic agent is a DPP4 inhibitor,

such as saxagliptin, sitagliptin, alogliptin, linagliptin. In some embodiments, the additional

therapeutic agent is a sodium glucose cotransporter type 2 (SGLT-2) inhibitor such as

dapagliflozin propanediol. In some embodiments, the additional therapeutic agent is a

fractalkine receptor inhibitor such as KAND-567.

[0300] In some embodiments, the additional therapeutic agent is an alpha2-receptor agonist.

For example, the additional therapeutic agent is dexmedetomidine.

[0301] In some embodiments, the additional therapeutic agent is a mCBM40 (multivalent

carbohydrate-binding module Family 40 domain) product, for example the additional therapeutic

agent is neumifil.

[0302] In some embodiments, the additional therapeutic agent is a histamine H1 receptor

antagonist, such as ebastine. In some embodiments, the additional therapeutic agent is tranilast.

In some embodiments, the additional therapeutic agent is a histamine H2 receptor antagonist. In

some embodiments, the additional therapeutic agent is famotidine. In some embodiments, the

additional therapeutic agent is anti-histamine. In some embodiments, the additional therapeutic

agent is cloroperastine or clemastine.

[0303] In some embodiments, the additional therapeutic agent is a vasoactive intestinal

peptide receptor 1 agonists, such as aviptadil.

[0304] In some embodiments, the additional therapeutic agent is a drug that treats acute

respiratory distress syndrome (ARDS).

[0305] In some embodiments, the additional therapeutic agent is a peptide, for example the

additional therapeutic agent is BIG-11006. In some embodiments, the additional therapeutic

agent is aliposomal formulation, for example the additional therapeutic agent is LEAF-4L6715,

LEAF-4L7520. In some embodiments, the additional therapeutic agent is a respiratory stimulant,

such as almitrine. In some embodiments, the additional therapeutic agent is a bronchodilator,

such as brensocatib or formoterol. In some embodiments, the additional therapeutic agent is an

anti-LIGHT antibody, such as CERC-002. In some embodiments, the additional therapeutic

agent is a CRAC (calcium release-activated calcium) channel inhibitor, such as CM-4620-IE.

[0306] In some embodiments, the compounds described herein are used in combination with

respiratory-specific small interfering RNA therapies. In some embodiments, these therapies are

delivered by a nebulizer.

[0307] In some embodiments, the additional therapeutic agent is a vimentin modulators. For

example, the additional therapeutic agent is pritumumab. In some embodiments, the additional

therapeutic agent is hzVSF-v13.

[0308] In some embodiments, the additional therapeutic agent is a modulator of Nsp15

(nonstructural protein 15) such as benzopurpurin B, C-467929, C-473872, NSC-306711 and N

65828.

[0309] In some embodiments, the additional therapeutic agent is a xanthine dehydrogenase

inhibitor, such as oxypurinol (XRx-101).

[0310] In some embodiments, the additional therapeutic agent is a cathepsin L-inhibitor. In

some embodiments, the additional therapeutic agent is a cathepsin inhibitor, such as VBY-825

or ONO-5334.

[0311] In some embodiments, the additional therapeutic agent is a Transforming growth factor

beta (TGF-) inhibitor. For example, the additional therapeutic agent is OT-101.

[0312] In some embodiments, the additional therapeutic agent is a N-methyl-D-aspartate

(NMDA) receptor antagonist. For example, the additional therapeutic agent is ifenprodil.

[0313] In some embodiments, the additional therapeutic agent is a glycolysis inhibitor. For

example, the additional therapeutic agent is WP-1122.

[0314] In some embodiments, the additional therapeutic is a Leukotriene D4 antagonist, such

as montelukast. In some embodiments, the additional therapeutic is a Leukotriene BLT receptor

antagonist, such as ebselen. In some embodiments, the additional therapeutic is a tubulin

inhibitor, such as VERU-111 or colchicine. In some embodiments, the additional therapeutic

agent is a glucosylceramide synthase inhibitor such as miglustat. In some embodiments, the

additional therapeutic agent is a Nrf2 activator, such as PB125. In some embodiments, the

additional therapeutic agent is a Rev protein modulator, such as ABX464. In some

embodiments, the additional therapeutic agent is a nuclear import inhibitor, such as iCP-NI (CV

). In some embodiments, the additional therapeutic agent is a cannabinoid CB2 receptor

1 ql agonist, such as PPP003. In some embodiments, the additional therapeutic agent is a dehydropeptidase-1 modulator, such as LSALT peptide. In some embodiments, the additional therapeutic agent is a cyclooxygenase inhibitor, such as celecoxib, naproxen, aspirin/dipyridamole. In some embodiments, the additional therapeutic agent is an antitoxin such as CALO2. In some embodiments, the additional therapeutic agent is a nitric oxide stimulant, such as GLS-1200. In some embodiments, the additional therapeutic agent is an apelin receptor agonist, such as CB-5064. In some embodiments, the additional therapeutic agent is a complement inhibitor, such as ravulizumab. In some embodiments, the additional therapeutic agent is a colony-stimulating factor 1 receptor (CSF1R) inhibitor, such as avdoralimab. In some embodiments, the additional therapeutic agent is a complement C5 factor inhibitor, such as eculizumab, zilucoplan, and C5a such as BDB-001, IFX-1, advoralimab, In some embodiments, the additional therapeutic agent is a complement C1s inhibitor, such as conestat alpha. In some embodiment, the additional therapeutic agent is a C3 inhibitor, such as APL-9 or AMY-101. In some embodiments, the additional therapeutic agent is an anti-C5aR antibody, such as advoralimab. In some embodiments, the additional therapeutic agent is an anti-elongation factor

1 alpha 2 inhibitor, such as plitidepsin. In some embodiments, the additional therapeutic agent is

an angiopoietin ligand-2 inhibitor, such as LY-3127804. In some embodiments, the additional

therapeutic agent is a lysine specific histone demethylase 1 inhibitor, such as vafidemstat. In

some embodiments, the additional therapeutic agent is a hyaluronan inhibitor. In some

embodiments, the additional therapeutic agent is a proton pump inhibitor, such as omeprazole.

[0315] In some embodiments, the additional therapeutic agent is an anti-viroporin therapeutic.

For example, the additional therapeutic agent is BIT-314 or BIT-225. In some embodiments, the

additional therapeutic agent is coronavirus E protein inhibitor. For example, the additional

therapeutic agent is BIT-009. Further examples of additional therapeutic agents include those

described in WO-2004112687, WO-2006135978, WO-2018145148, and WO-2009018609.

11A

[0316] In some embodiments, the compounds disclosed herein are used in combination with

cell therapy, such as allogeneic natural killer cells, BM-Allo.MSC, CAStem, IL-15-NK cells,

NKG2D- CAR-NK cells, ACE2 CAR-NK cells, partially HLA-matched Virus Specific T cells

(VSTs), RAPA-501, or SARS-CoV-2 Specific T Cells.

[0317] It is also possible to combine any compound of the invention with one or more

additional active therapeutic agents in a unitary dosage form for simultaneous or sequential

administration to a patient. The combination therapy may be administered as a simultaneous or

sequential regimen. When administered sequentially, the combination may be administered in

two or more administrations.

[0318] Co-administration of a compound of the invention with one or more other active

therapeutic agents generally refers to simultaneous or sequential administration of a compound

of the invention and one or more other active therapeutic agents, such that therapeutically

effective amounts of the compound of the invention and one or more other active therapeutic

agents are both present in the body of the patient.

[0319] Co-administration includes administration of unit dosages of the compounds of the

invention before or after administration of unit dosages of one or more other active therapeutic

agents, for example, administration of the compounds of the invention within seconds, minutes,

or hours of the administration of one or more other active therapeutic agents. For example, a

unit dose of a compound of the invention can be administered first, followed within seconds or

minutes by administration of a unit dose of one or more other active therapeutic agents.

Alternatively, a unit dose of one or more other therapeutic agents can be administered first,

followed by administration of a unit dose of a compound of the invention within seconds or

minutes. In some cases, it may be desirable to administer a unit dose of a compound of the

invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be desirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.

[0320] The combination therapy may provide "synergy" and "synergistic", i.e. the effect

achieved when the active ingredients used together is greater than the sum of the effects that

results from using the compounds separately. A synergistic effect may be attained when the

active ingredients are: (1) co-formulated and administered or delivered simultaneously in a

combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3)

by some other regimen. When delivered in alternation therapy, a synergistic effect may be

attained when the compounds are administered or delivered sequentially, e.g. in separate tablets,

pills or capsules, or by different injections in separate syringes. In general, during alternation

therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially,

whereas in combination therapy, effective dosages of two or more active ingredients are

administered together. A synergistic anti-viral effect denotes an antiviral effect which is greater

than the predicted purely additive effects of the individual compounds of the combination.

[0321] In still yet another embodiment, the present application provides for methods of

inhibiting a 2019-nCoV polymerase in a cell, comprising: contacting a cell infected with 2019

nCoV with an effective amount of a compound of Formula I-IV, or a pharmaceutically

acceptable salt, solvate, and/or ester thereof, whereby the 2019-nCoV polymerase is inhibited.

[0322] In still yet another embodiment, the present application provides for methods of

nCoV with an effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent, whereby the 2019-nCoV polymerase is inhibited.

[0323] In still yet another embodiment, the present application provides for methods of

treating a 2019-nCoV virus infection in a human, comprising: administering to the patient a

therapeutically effective amount of a compound of Formula I-IV, or a pharmaceutically

acceptable salt, solvate, and/or ester thereof.

[0324] In still yet another embodiment, the present application provides for methods of

acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent,

whereby a 2019-nCoV polymerase is inhibited.

[0325] In still yet another embodiment, the present application provides for methods of

acceptable salt, solvate, and/or ester thereof, and at least one additional active therapeutic agent.

[0326] Also provided is a kit that includes a compound of Formula I, or a pharmaceutically

acceptable salt, pharmaceutically acceptable ester, stereoisomer, mixture of stereoisomers or

tautomer thereof. In separate embodiments individual kits are provided includes a compound

selected from the group of each of the Formulas herein, as well as each subgroup and

embodiment thereof, including Formula II, Formula II, Formula IV, and individual Compounds

1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,

, 31, and 32 (Compounds 1-32), or a pharmaceutically acceptable salt, pharmaceutically

acceptable ester, stereoisomer, mixture of stereoisomers or tautomer thereof. In one aspect, the

kit comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof. Each of the individual kits described herein may comprise a label and/or instructions for use of the compound in the treatment of a disease or condition in a subject (e.g., human) in need thereof.

In some embodiments, the disease or condition is a human 2019-nCoV infection. In other

embodiments, each separate kit may also contain instructions for use of additional medical

agents in combination with the compound of Formula I in the treatment of a disease or condition

in a subject (e.g., human) in need thereof. In certain of these embodiments, the disease or

condition is a human 2019-nCoV infection. In each of the kits herein there is a further

embodiment in which the kit comprises individual dose units of a compound as described herein,

or a pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph,

pseudopolymorph, amorphous form, hydrate or solvate thereof. Examples of individual dosage

units may include pills, tablets, capsules, prefilled syringes or syringe cartridges, IV bags, etc.,

each comprising a therapeutically effective amount of the compound in question, or a

pharmaceutically acceptable salt, racemate, enantiomer, diastereomer, tautomer, polymorph,

pseudopolymorph, amorphous form, hydrate or solvate thereof. In some embodiments, the kit

may contain a single dosage unit and in others multiple dosage units are present, such as the

number of dosage units required for a specified regimen or period.

[0327] Also provided are articles of manufacture that include a compound of Formula I, or a

pharmaceutically acceptable salt, pharmaceutically acceptable ester, stereoisomer, mixture of

stereoisomers or tautomer thereof; and a container. In one aspect, the article of manufacture

comprises a compound of Formula I, Formula II, Formula II, Formula IV, and individual

Compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,

26, 27, 28, 29, 30, 31, and 32 (Compounds 1-32), or a pharmaceutically acceptable salt thereof,

and a container. In separate embodiments, the container of the article of manufacture may be a

vial, jar, ampoule, preloaded syringe, blister package, tin, can, bottle, box, or an intravenous bag.

11A

[0328] Also provided as separate embodiments are the uses of a compound selected from each

of the Formulas herein, as well as each subgroup and embodiment thereof, including a

compound selected from the group of Formula (I), Formula (II), Formula (III), Formula (IV), or

one of the specific compounds of the examples herein, including Compounds 1-32, or a

pharmaceutically acceptable salt, solvate, and/or ester thereof, in the preparation of a

medicament for use in treating a 2019-nCoV infection in a human.

6. METHODS OF INHIBITION OF 2019-NCOV POLYMERASE

[0329] Another aspect of the invention relates to methods of inhibiting the activity of 2019

nCoV polymerase comprising the step of treating a sample suspected of containing 2019-nCoV

with a compound or composition of the invention.

[0330] Compositions of the invention may act as inhibitors of 2019-nCoV polymerase, as

intermediates for such inhibitors or have other utilities as described below. The inhibitors will

bind to locations on the surface or in a cavity of 2019-nCoV polymerase having a geometry

unique to 2019-nCoV polymerase. Compositions binding 2019-nCoV polymerase may bind

with varying degrees of reversibility. Those compounds binding substantially irreversibly are

ideal candidates for use in this method of the invention. Once labeled, the substantially

irreversibly binding compositions are useful as probes for the detection of 2019-nCoV

polymerase. Accordingly, the invention relates to methods of detecting 2019-nCoV polymerase

in a sample suspected of containing 2019-nCoV polymerase comprising the steps of: treating a

sample suspected of containing 2019-nCoV polymerase with a composition comprising a

compound of the invention bound to a label; and observing the effect of the sample on the

activity of the label. Suitable labels are well known in the diagnostics field and include stable

free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.

The compounds herein are labeled in conventional fashion using functional groups such as

hydroxyl, carboxyl, sulfhydryl or amino.

[0331] Within the context of the invention, samples suspected of containing 2019-nCoV

polymerase include natural or man-made materials such as living organisms; tissue or cell

cultures; biological samples such as biological material samples (blood, serum, urine,

cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food,

water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells

synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of

containing an organism which produces 2019-nCoV polymerase, frequently a pathogenic

organism such as an 2019-nCoV virus. Samples can be contained in any medium including

water and organic solvent\water mixtures. Samples include living organisms such as humans,

and manmade materials such as cell cultures.

[0332] The treating step of the invention comprises adding the composition of the invention to

the sample or it comprises adding a precursor of the composition to the sample. The addition

step comprises any method of administration as described above.

[0333] If desired, the activity of 2019-nCoV polymerase after application of the composition

can be observed by any method including direct and indirect methods of detecting 2019-nCoV

polymerase activity. Quantitative, qualitative, and semiquantitative methods of determining

2019-nCoV polymerase activity are all contemplated. Typically one of the screening methods

described above are applied, however, any other method such as observation of the

physiological properties of a living organism are also applicable.

[0334] Organisms that contain 2019-nCoV polymerase include the 2019-nCoV virus. The

compounds of this invention are useful in the treatment or prophylaxis of 2019-nCoV infections

in animals or in man.

[0335] However, in screening compounds capable of inhibiting human 2019-nCoV viruses, it

should be kept in mind that the results of enzyme assays may not correlate with cell culture

assays. Thus, a cell based assay should be the primary screening tool.

[0336] In another embodiment, the present application provides for methods of treating 2019

nCoV virus infection in a human, comprising: administering to the patient a therapeutically

effective amount of a compound of Formula I-IV, or a pharmaceutically acceptable salt, solvate,

and/or ester thereof. In some embodiments, the 2019-nCoV infection is caused by 2019-nCoV.

In some embodiments, the 2019-nCoV polymerase is inhibited.

[0337] The compounds of the present invention can be used in the treatment of a human

already suffering from a 2019-nCoV infection, or can be administered prophylactically to reduce

or prevent the chance of a 2019-nCoV infection. Physical examination of patients infected with

2019-nCoV after the onset of fever may reveal purulent pharyngitis, bilateral conjunctival

hemorrhages, facial edema, and generalized abdominal tenderness. Macroscopic pathological

changes can include pleural effusions, pulmonary edema, ascites, and hemorrhagic

manifestations in the gastrointestinal mucosa.

7. SCREENS FOR 2019-NCOV POLYMERASE INHIBITORS.

[0338] Compositions of the invention are screened for inhibitory activity against 2019-nCoV

polymerase by any of the conventional techniques for evaluating enzyme activity. Within the

context of the invention, typically compositions are first screened for inhibition of 2019-nCoV

polymerase in vitro and compositions showing inhibitory activity are then screened for activity

in vivo.

[0339] Useful in vitro screens will not be elaborated here. However, the examples describe

suitable in vitro assays.

8. EXAMPLES

1. Preparation of Compounds

[0340] The compounds described herein can be prepared by known methods. For example, by

methods disclosed in W02017/049060. Following are exemplary compounds prepared.

i. (2R,3R,4S,5R)-2-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-3,4-dihydroxy-5

(hydroxymethyl)tetrahydrofuran-2-carbonitrile(Compound1)

NH 2

N HO-,H

ii. (2R,3R,4R,5R)-2-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-3-fluoro-4-hydroxy-5 (hydroxymethyl)tetrahydrofuran-2-carbonitrile(Compound2) NH 2

N HO N, O N 'CN HO' F

2

iii. (2R, 3R, 4R, 5S)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-4-fluoro-2 (hydroxymethyl)-5-methyltetrahydrofuran-3-ol (Compound 3) NH 2

*-N HO N

H6d 'F 3

iv. 2R)-isopropyl 2-((((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-4 fluoro-3-hydroxy-5-methyltetrahydrofuran-2-yl)methoxy) (phenoxy)phosphorylamino)propanoate (Compound 4)

11AdA

NH 2

NN~ o N

o HI OPh HO 'F

4

v. (2R)-ethyl 2-((((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-4-fluoro 3-hydroxy-5-methyltetrahydrofuran-2 yl)methoxy)(phenoxy)phosphorylamino)propanoate(Compound5) NH 2

N

O OON' O0 OPh .

Hd IF

5

vi. ((2R,3R,4R,5S)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-4-fluoro-3-hydroxy-5 methyltetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 6) NH 2

O -0 N HO' 'O I OH OH OH '

6

vii. (2R,3R,5S)-2-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-3-hydroxy-5 (hydroxymethyl)-tetrahydrofuran-2-carbonitrile (Compound 7) NH 2

N HO \ N'N '''CN

OH 7

viii. (2S)-isopropyl 2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy) phosphorylamino)propanoate (Compound 8)

1 AS

NH 2

NN O O-P-O NH : HN

8

ix. (2S)-2-ethylbutyl 2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphorylamino)propanoate (Compound 9) NH 2

`;N

O O-P-O O NH H

9

x. (2S)-ethyl 2-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-f][1,2,4]triazin-7-yl)-5-cyano 3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphorylamino)propanoate (Compound 10)

O NH 2

O- ON N N

O N 0' O0 Hd 'OH

10

xi. (2S)-ethyl 2-((((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5-cyano 4-fluoro-3-hydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphorylamino)propanoate (Compound 11) NH 2

'-N O O-P-O NH HN

1iti 11 xii. (2S,2'S)-diethyl 2,2'-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)phosphoryl)bis(azanediyl)dipropanoate (Compound 12) NH 2 N 0O N, N o OHN-P-O NH N HO OH Ol 12 xiii. (2S,3R,4S,5R)-2-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-2-ethynyl-5 (hydroxymethyl)tetrahydrofuran-3,4-diol (Compound 13) NH 2

-N HO \ N

Hd OH 13

xiv. (2R,3R,4R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-1,3,4-tris(benzyloxy)hexane 2,5-diol (Compound 14) NH 2

N, HO 0 N'N

Hd OH 14

xv. S,S'-2,2'-((((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5-cyano-3,4 dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1-diyl) bis(2,2-dimethylpropanethioate)(Compound15) NH 2 SN

0P- N 'ON HO OH 15

1d7 xvi. S,S'-2,2'-((((2R, 3S, 4R, 5S)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5-ethynyl 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)phosphoryl)bis(oxy)bis(ethane-2,1 diyl) bis(2,2-dimethylpropanethioate) (Compound 16) NH 2

S N N, 0-P-O I O 0 'N O -0

HO OH 16

xvii. ((2R,3S,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5-cyano-3,4 dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 17) NH 2

H0 00o 0 N HO' O'O0 OHx OHX OH "ON

HG OH 17

xviii. ((2R, 3S, 4R, 5S)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-5-ethynyl-3,4 dihydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 18) NH 2

000r

Hd OH 18 \NH2 - o N xix. ((2R,3S,4R,5S)-5-(4-aminopyrrolo[1,2-fl[1,2,4]triazin-7-yl)-3,4-dihydroxy-5 HOP0-0 --O O N OH OH OH methyltetrahydrofuran-2-yl)methy tetrahydrogen triphosphate (Compound 19) NH 2

0 0 -T N O HO-P-O-P-O-P-O 0 N OH OH OH

H6 OH 19

xx. ((2R,3R,4R,5R)-5-(4-aminopyrrolo[1,2-fl[1,2,4ltriazin-7-yl)-5-cyano-4-fluoro-3 hydroxytetrahydrofuran-2-yl)methyl tetrahydrogen triphosphate (Compound 20)

NH 2

HO'O'>O' ' O N H OH OH "O'CN HdF 20

xxi. (2S)-ethyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-fl[1,2,4]triazin-7-yl)-5-cyano 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3 phenylpropanoate(21) NH 2

'O N

0- - OON' -'CN NH Ho oH

21

xxii. (2S)-ethyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-fl[1,2,4]triazin-7-yl)-5-cyano 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-3 methylbutanoate (22)

NH 2

00-P- -,\ NN 0O - I '- ,CN NH H5 oH 22

xxiii. (S)-isopropyl 2-(((R)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-fl[1,2,4]triazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphoryl)amino)propanoate(23) NH 2

Q N op-o N 0 'CN NH H6 H

23

1iQ xxiv. (2S)-cyclobutyl 2-(((((2R,3S,4R,5R)-5-(4-arninopyrrolo[2,1-fl[1,2,4ltriazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)rnethoxy)(phenoxy)phosphoryl)arnino)propanoate (24) NH 2

0N PhO-P-O-- N HN<

00 - OH

24

xxv. (2S)-isopropyl 2-(((((2R,3S,4R,5R)-5-(4-arninopyrrolo[2,1-fl[1,2,4ltriazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2-yl)nethoxy)(phenoxy)phosphoryl)anino)-3 phenyipropanoate (25) NH 2

IQ 1

N H. I~~KNN - ~ HO O

25

xxvi. (S)-rnethyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-arninopyrrolo[2,1-fl[1,2,4ltriazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)rnethoxy)(phenoxy)phosphoryl)arnino)propanoate (26) 0 NH 2 o H 0 N 0N

26

xxvii. (S)-neopentyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-arninopyrrolo[2,1-fl[1,2,4ltriazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)rnethoxy)(phenoxy)phosphoryl)arnino)propanoate (27)

1 Sfl

S NH 2 H O N, N

\N J O OHN IHd OH

27

xxviii. (2S)-cyclopentyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-fl[1,2,4]triazin-7-yl) 5-cyano-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (28)

O 60'N o O N N

p- N Hd 'OH

28

xxix. (2S)-cyclohexyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-fl[1,2,4]triazin-7-yl)-5 cyano-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (29)

NH 2 O H 60 O O N

Hd bH

29

xxx. Ethyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4 dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2 methylpropanoate(30) NH 2

N HO N' 0°-- 'CN

30

1S1 xxxi. Isopropyl 2-(((((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano 3,4-dihydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)-2 methylpropanoate(31) NH 2

N O | 'CN O NY HO OH

31

xxxii. (S)-2-ethylbutyl 2-(((S)-(((2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) 5-cyano-3,4-dihydroxytetrahydrofuran-2 yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (32) NH 2

0N 0 ~ N N

) o HN-F -O O 0 N I HO OH

Compound 32

2. Antiviral Activity

[0341] Another aspect of the invention relates to methods of inhibiting 2019-nCoV infections,

comprising the step of treating a sample or subject suspected of needing such inhibition with a

composition of the invention.

[0342] Within the context of the invention samples suspected of containing a virus include

natural or man-made materials such as living organisms; tissue or cell cultures; biological

samples such as biological material samples (blood, serum, urine, cerebrospinal fluid, tears,

sputum, bronchoalveolar lavage, nasal swab, nasal wash, saliva, tissue samples, and the like);

laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells,

particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the

sample will be suspected of containing an organism which induces a viral infection, frequently a

pathogenic organism such as a tumor virus. Samples can be contained in any medium including

1W ) water and organic solvent\water mixtures. Samples include living organisms such as humans, and man made materials such as cell cultures.

[0343] If desired, the anti-virus activity of a compound of the invention after application of the

composition can be observed by any method including direct and indirect methods of detecting

such activity. Quantitative, qualitative, and semiquantitative methods of determining such

activity are all contemplated. Typically one of the screening methods described herein are

applied, however, any other method such as observation of the physiological properties of a

living organism are also applicable.

[0344] The antiviral activity of a compound of the invention can be measured using

appropriate screening protocols.

Example 1: 2019-nCoV antiviral assay

[0345] Vero E6 cells are seeded in 384-well plates and serial dilutions of Compound 32 or

Compound 9 are added to the assay plates by direct titration using an HP D300 Digital

Dispenser (Hewlett-Packard, Palo Alto, CA). The plates are infected with 2019-nCoV at a

multiplicity of infection of 0.5 plaque forming unit (pfu) per cell. The infected cultures are

incubated for 48 hours. The level of virus replication in compound-treated and control vehicle

treated cultures is determined by quantifying the level of virus-specific antigen following

immuno-staining with antibody against the 2019-nCoV spike (S) protein. The primary antibody

is diluted 1000-fold in blocking buffer (lx phosphate buffered saline (PBS) with 3% BSA) and

added to each well of the assay plate. The assay plates are incubated for 60 minutes at room

temperature. The primary antibody is removed and the cells are washed 3 times with lx PBS.

The secondary detection antibody is an anti-rabbit IgG conjugated with Dylight488 (Thermo

Fisher Scientific, Waltham, MA, Cat# 405310). The secondary antibody is diluted 1000-fold in

blocking buffer and is added to each well in the assay plate. The assay plates are incubated for minutes at room temperature. Nuclei are stained using Draq5 (Biostatus, Shepshed

Leicestershire, UK, Cat# DR05500) diluted in lx PBS. The cells are counter-stained with

CellMask Deep Red (Thermo Fisher Scientific, Waltham, MA, Cat# C10046) to enhance

detection of the cytoplasm compartment. Cell images are acquired using Perkin Elmer Opera

confocal microscope (Perkin Elmer, Waltham, MA) using lOx air objective to collect 5 images

per well. Virus-specific antigen is quantified by measuring fluorescence emission at a 488 nm

wavelength and the nuclei are quantified by measuring fluorescence emission at a 640 nm

wavelength. High content image analysis is performed to quantify the percent of infected cells

and cell viability. Analysis of dose response to determine EC5 o values is performed using

GeneData Screener software applying Levenberg-Marquardt algorithm for curve fitting strategy.

Example 2: 2019-nCoV antiviral assay

[0346] HAE cell cultures isolated from lung tissue are cultured for up to 6 weeks at the air

liquid interface to promote differentiation (Zhu et al. NEJM Jan 24, 2020). The apical surfaces

of the HAE cultures are washed at 24 h and 1 h prior to infection with lx PBS for >1 hour at 37

°C. Recombinant 2019-nCoV expressing red fluorescent protein (2019-nCoV RFP) are used to

apically infect the differentiated HAE cultures at a multiplicity of infection of 0.1 pfu per cell.

To infect the HAE cultures, apical washes are removed, viral inoculum is added, and inoculated

cultures are incubated at 37 °C for 2.5 hours. The inoculum is removed, and the apical surfaces

of the HAE cultures are washed 3 times with 500 pL of lx PBS to remove residual virus. Five 3

fold serial dilutions of Compound 9 starting at 10 tM are prepared in triplicate and added to

HAE ALI media on the basolateral side of the culture approximately 30 minutes prior to

infection. Virus replication is assessed by fluorescence imaging of cell cultures following a 48

hour incubation. In addition, virus replication is quantified by measuring the production of

infectious virus in HAE apical washes by plaque assay on Vero cell monolayers and by

1 Sd1 quantifying viral RNA production from total cell RNA by real-time PCR assay.

Example 3: 2019-nCoV real-time PCR assay

[0347] At 48 hours post-infection, primary HAE cultures from the antiviral assay described

above are harvested in 500 pL TRIzol. RNA is purified using a Direct-zol RNA MiniPrep kit

(Zymo Research Corporation, Irvine, CA, USA). First-strand cDNA is generated for each

sample using SuperScript III (Life Technologies, Grand Island, NY, USA) with incubation at 55

°C. Following first-strand cDNA generation, 2019-nCoV subgenomic RNA are quantified by

real-time PCR using appropriate primers. Reads are normalized to GAPDH using the following

primers: GAPDH Forward (5'- TGC ACC AAC TGC TTA GC -3') and GAPDH Reverse (5'

GGC ATG GAC TGT GGT CAT GAG -3'). Results are expressed as log10 fold changes in

viral 2019-nCoV encoding RNA copy number in treated versus untreated cells using the AACt

method {10431}.

Example 4: In vitro efficacy in Calu-3 2B4 Cells

[0348] At 48 hrs prior to infection, Calu-3 2B4 cells are plated in a 96-well black walled clear

bottom plate at 5 x104 cells/well. 24-hr prior to infection, culture medium is replaced. A 20 mM

stock of Compound 32 is serially diluted in 100% DMSO in 3-fold increments to obtain a ten

point dilution series. 2019-nCoV-nLUC is diluted in DMEM 10% FBS, and 1%

antibiotics/antimycin to achieve a multiplicity of infection (MOI) of 0.08. Cells are infected in

triplicate per drug dilution for 1 hr after which, virus is aspirated, cultures are rinsed once and

fresh medium containing drug or vehicle is added. At 48 hrs post infection, virus replication is

quantitated on a Spectramax (Molecular Devices) plate reader via nano-luciferase assay

(Promega) according to the manufacturer's protocol. For our 100% inhibition control, diluted

2019-nCoV-nLUC is exposed to short-wave UV light (LLC, Upland, CA) for 6 minutes to inhibit the ability of the virus to replicate. For our 0% inhibition control, cells are infected in the presence of vehicle. DMSO is kept constant in all conditions at 0.05% by volume (v/v). Values from triplicate wells per condition are averaged and compared to controls to generate a percent inhibition value for each drug dilution. The EC5 o value is defined as the concentration at which there is a 50% decrease in viral replication. Data are analyzed using GraphPad Prism 6.0 (La

Jolla, CA). The EC5 o and CC 5 o values are calculated by non-linear regression analysis using the

dose-response (variable slope) equation (four parameter logistic equation): Y = Bottom + (Top

Bottom)/(1+10A((LogEC 5 o-X)*HillSlope)). The "Bottom" and "Top" values are defined by the

minimum and maximum Y values. Hill slope is a parameter used to define the steepness of a

dose-response curve. ECo and CC 5 values are calculated as an average of two to four

independent experiments.

Example 5: Evaluation of Subcutaneous Compound 32 against 2019-nCoV in Esterase

Deficient (Cesic-l- ) Mice

[0349] Male and female mice (25-28 week) are genetically deleted for carboxylesterase 1C

(Cesic-- ) (Jackson Laboratories stock 014096). The (Cesic-- ) mice are used since rodents

express high levels of carboxylesterase activity in plasma relative to other animal species

reducing the plasma half-life of Compound 32. Genetic deletion of carboxylesterase 1C improvs

the plasma stability of Compound 32 generating pharmacokinetic profiles similar to those

observed in humans and other animal species.

[0350] The study design is captured in Table 1. Efficacy studies are performed in an animal

biosafety level 3 (ABSL3) facility.

Table 1: Experimental Design (Subcutaneous Injection)

Compound #Males/ Timing and Group Treatment 32 Dose Challenge #Females Duration (mg/kg)

Twice Daily, D-1 1 6/6 Vehicle 0 toD5

Compound Twice Daily, D-1 2 4/4 25 2019-nCoV 32 in vehicle to D5

Compound Once Daily, D-1 3 6/6 50 32 in vehicle to D5

Twice Daily, D-1 4 1/2 Vehicle 0 toD5 No virus Compound Twice Daily, D-1 2/1 25 32 in vehicle to D5

[0351] Groups 1 (vehicle), Group 2 (Compound 32 BID 25 mg/kg), and Group 3 (Compound

32 QD 50 mg/kg) are anaesthetized with ketamine/xylazine and exposed to 10 4 pfu of 2019

nCoV /50ul via the intranasal route. Group 4 (Vehicle) and Group 5 (Compound 32 BID 25

mg/kg) remain uninfected and are used as controls for whole body plethysmography evaluations.

Vehicle comprises 12% sulfobutylether--cyclodextin in water (with HCl/NaOH) at pH 5.0). On

day 0, animals are exposed to virus. On days 2 and 5 post infection, groups of animals are

euthanized by isofluorane overdose and the large left lobe of the lung is placed in a 2 mL screw

cap tube with 1 mL DPBS with glass beads and frozen at -80 °C until analyzed by plaque assay.

The inferior right lobe is placed in 10% buffered formalin and stored at 4 °C until histological

analysis.

1 S7

[0352] Changes in lung function are determined by whole body plethysmography (WBP,

Buxco lung function testing system, Data Sciences International). After a 30-minute acclimation

in the plethysmograph chamber, 11 respiratory responses and several quality control metrics are

continually measured every 2-second for 5 minutes for a total of 150 data points. Mean values

for each parameter are determined within DSI Finepoint software.

[0353] Histological analysis is performed on formalin fixed samples and paraffin embedded

tissues with 5pm. To assess lung pathology, sections are stained with hematoxylin and eosin.

Viral antigen in the lung is stained using polyclonal anti-nucleocapsid antibody (Imgenex).

Slides are blinded to the evaluator and assessed for virus associated lung pathology as well as

spatial location and prevalence of viral antigen. Images are captured using an Olympus BX41

microscope equipped with an Olympus DP71 camera.

[0354] Viral plaque assay is used to quantify infectious virus from frozen lung tissue. Vero E6

cells are seeded in 6-well plates at 5 x 10 5 cells /well. Lung tissue is thawed, homogenized via

Roche Magnalyzer, and the tissue suspension is serially diluted and the dilutions are used to

infect the Vero E6 cells. At 72 h post-infection, the plates are fixed and stained and the number

of plaques quantified by visual inspection.

[0355] The primary endpoint for this study is viral load in lung tissue at Day 5 post-infection.

Additional endpoints include changes in animal body weight and lung function. Animal body

weight is recorded daily for the duration of the in-life phase. On day -1, 1, 2, 3, and 5 after

inoculation, whole body plethysmography is performed to assess lung function. On Day 5, a

scheduled necropsy is performed on all remaining animals; gross lung pathology is evaluated by

a board-certified veterinary pathologist. Lung tissue is collected for histopathological and

virological analysis.

[0356] Body Weight and Viral Load: Changes in body weight and tissue viral load for each

study group at Day 5 are recorded.

[0357] Lung Function Measurements: The effect of Compound 32 treatment on pulmonary

function in 2019-nCoV infected mice is evaluated by whole body plethysmography (WBP).

Example 6: A Blinded, Randomized, Vehicle-Controlled Evaluation of Intravenous

Compound 32 against 2019-nCoV in Rhesus Monkeys

[0358] 2019-nCoV isolate is used for the challenge virus at the Test Facility. 2019-nCoV is

propagated in VeroE6 cells in DMEM (Sigma) supplemented with 2% (vol/vol) FCS (Logan), 1

mM L-glutamine (Lonza), 50 U/mL penicillin, and 50 [g/mL streptomycin (Gibco).

Experimentally naive male rhesus monkeys are randomly assigned to treatment groups and

balanced by body weight.

[0359] The study design is captured in Table 2.

Table 2: Experimental Design (Intravenous)

#Males/ Compound 32 Group Treatment Timing and Duration* Challenge #Females Dose (mg/kg)

1 6/0 Vehicle 0 Once Daily, D-1 to D6

Compound 32 in 2 6/0 10 Once Daily, D-1 to D6 vehicle 2019-nCoV

Compound 32 in 3 6/0 10 Once Daily, D1 to D6 vehicle

[0360] All animals are exposed to a target dose of 7x10 6 plaque forming units 2019-nCoV

virus diluted in 0.9% sodium chloride for inoculation. The animals are inoculated by multiple

routes that included intranasal, ocular, and intratrachial administration. The day on which

animals are challenged is designated as Day 0.

1 S0

[0361] Methods to control bias include experimental blinding. Specifically, study personnel

who administer Compound 32 or vehicle treatments or routinely evaluated animal health are

experimentally blinded to the group assignment of all animals for the duration of the in-life

phase. Unblinded personnel, who are not responsible for evaluating animal health, prepare

individual doses from bulk ready-to-use formulations provided by the Sponsor. Vehicle and

Compound 32 formulations are identical in physical appearance.

[0362] In Groups 1 and 2, once-daily vehicle treatment is administered for 7 days beginning

on Day -1 (one day prior to virus exposure). In Group 3, once-daily vehicle treatment is

administered for 7 days beginning on Day 1 (12 to 24 hours after virus exposure). Each dose of

Compound 32 or vehicle is administered as a single bolus slow IV injection in the saphenous

vein at a volume of 2.0 mL/kg body weight over the course of 1 to 2 min. Doses are

administered to animals anesthetized using IM injection of a solution containing ketamine (100

mg/mL) and acepromazine (10 mg/mL) at a volume of 0.1 mL/kg body weight. The weight of

each animal is obtained on Day -7, and these weights are used for dose volume determination for

all administered doses of Compound 32 or vehicle.

[0363] The primary endpoint for this study is viral load in lung tissue at Day 6 post-infection.

Animal health is monitored at least twice daily for the duration of the in-life phase and clinical

disease signs are recorded. On day -7, 0, 1, 3, 5 and 6 after inoculation, clinical exams are

performed on all animals to determine bodyweight, body temperature, respirations/minute

(under anesthesia), and to collect x-rays, nose and throat swabs. Whole blood and serum are

collected for hematology, biochemistry and cytokine analysis. On Day 6, a scheduled necropsy

is performed on all animals; gross lung pathology is scored (as % of lung lobe affected by gross

lesions) by a board-certified veterinary pathologist and lung weight is recorded to determine the

lung weight/ body weight ratio. Nineteen tissues are collected for histopathological and

virological analysis.

1 A0

[0364] Disease signs in vehicle-treated animals are attributed to 2019-nCoV infection.

Cumulative clinical scores are notably higher in vehicle-treated animals compared to Compound

32-treated animals. These disease symptoms are less pronounced in the Compound 32-treated

animals.

[0365] Body Weight and Viral Load: Changes in body weight, temperature and respiration

are recorded.

[0366] Tissue Viral Load: Viral RNA is measured in lung tissue and other organs collected at

necropsy.

Example 7: SARS-CoV-2 antiviral assay

[0367] Antiviral activity of compounds against SARS-CoV-2 was evaluated as described in

Xue, Xi et al. 2020 (Xie, X. et al. (2020). A nanoluciferase SARS-CoV-2 for rapid

neutralization testing and screening of anti-infective drugs for COVID-19. Nat. Comm. bioRxiv

2020.06.22.165712; doi: https://doi.org/10.1101/2020.06.22.165712). Briefly, the human

alveolar epithelial cell line (A549) was maintained in a high-glucose DMEM supplemented with

% fetal bovine serum, 1% P/S and 1% HEPES (ThermoFisher Scientific). The A549-hACE2

cells that stably express human angiotensin-converting enzyme 2 (hACE2) were grown in the

culture medium supplemented with 10 tg/mL Blasticidin S (Mossel, E. C. et al. (2005).

Exogenous ACE2 expression allows refractory cell lines to support severe acute respiratory

syndrome coronavirus replication. J Virol 79, 3846-3850, doi:10.1128/JVI.79.6.3846

3850.2005). Cells were grown at 37°C with 5% C02. All culture medium and antibiotics were

purchased from ThermoFisher Scientific (Waltham, MA). All cell lines were tested negative for

mycoplasma. A549-hACE2 cells (12,000 cells per well in phenol-red free medium containing

2% FBS) were plated into a white opaque 96-well plate (Coming). On the next day, 2-fold serial

dilutions of compounds were prepared in DMSO. The compounds were further diluted 100-fold

1A1 in the phenol-red free culture medium containing 2% FBS. Cell culture fluids were removed and incubated with 50 L of diluted compound solutions and 50 L of SARS-CoV2-Nluc viruses

(MOI 0.025). At 48 h post-infection, 50 L Nano luciferase substrates (Promega) were added to

each well. Luciferase signals were measured using a SynergyTM Neo2 microplate reader. The

relative luciferase signals were calculated by normalizing the luciferase signals of the

compound-treated groups to that of the DMSO-treated groups (set as 100%). The relative

luciferase signal (Y axis) versus the logio values of compound concentration (X axis) was

plotted in software Prism 8. The EC5 o (compound concentration for reducing 50% of luciferase

signal) were calculated using a nonlinear regression model (four parameters). Two experiments

were performed with technical duplicates.

Example 8: A549 cytotoxicity analysis

[0368] The cytotoxicity of compounds was determined in A549 cells in the following manner.

Compounds (200 nL) were spotted onto 384-well Grenier plates prior to seeding 5000 A549

cells/well in a volume of 40 pL culture medium. The plates were incubated at 37 °C for 48

hours with 5% C02. On day 2, 40 pL of CellTiter-Glo (Promega) was added and mixed 5 times.

Plates were read for luminescence on an Envision (PerkinElmer) and the CC5 o (compound

concentration for reducing 50% of luminescence signal as a measure of cell viability) were

calculated using a nonlinear regression model (four parameters).

1A

SARS-CoV-2 (2- A549 Cytotoxicity (2

day) day) Compound EC5o n CC5o (pM) n (pM)

NH 2 N

S N, N 0.869 HO -CN 2 >50 2 - - 0.289 HO OH

Compound 1

NH 2 N 0 N ,)~ o -O N'N 0.135± IN 8 >25.2 10 O HO H 0.020

Compound 32

NH 2 0N O N, 0.272 o HN-ON 2 17.7 2 ~N 0.075 O Hd bH

[0369] Example 9: Combination Therapy

[0370] Eligible patients were randomly assigned in a 1:1 ratio to receive either remdesivir and

baricitinib or remdesivir and placebo. Randomization was stratified according to trial site and

disease severity at enrollment (Baricitinib plus Remdesivir for Hospitalized Adults with Covid

19; The New England Journal of Medicine, Dec. 11, 2020, DOI: 10.1056/NEJMoa231994).

1,'-V

Patients received remdesivir intravenously as a 200-mg loading dose on day 1, followed by a

100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or

death. Baricitinib was administered as a 4-mg daily dose (either orally [two 2-mg tablets] or

through a nasogastric tube) for 14 days or until hospital discharge. Patients with an estimated

glomerular filtration rate of less than 60 ml per minute received baricitinib at a dose of 2 mg

once daily. A matching oral placebo was administered according to the same schedule as the

active drug. All the patients received standard supportive care at the trial site hospital. Venous

thromboembolism prophylaxis was recommended for all the patients without a major

contraindication. If a hospital had a written policy for Covid-19 treatments, patients could

receive those treatments. In the absence of a written policy, other experimental treatment and

off-label use of marketed medications intended as specific treatment for Covid-19 were

prohibited. This included glucocorticoids, which were permitted only for standard indications

such as adrenal insufficiency, asthma exacerbation, laryngeal edema, septic shock, and acute

respiratory distress syndrome.

[0371] All patients were evaluated daily during their hospitalization, from day 1 through day

29. The trial team was unaware of the trial-group assignments until after all data queries were

resolved and the database was locked.

[0372] Patients who received combination treatment with baricitinib plus remdesivir

recovered a median of 1 day faster than patients who received remdesivir and placebo (median,

7 days vs. 8 days; rate ratio for recovery, 1.16; 95% confidence interval [CI], 1.01 to 1.32; P =

0.03 by log-rank test stratified according to actual baseline severity). When analyzed according

to the severity entered at the time of randomization (moderate vs. severe), the hazard ratio was

1.15 (95% CI, 1.00 to 1.31; P = 0.047). The median time to recovery among patients receiving

noninvasive ventilation or high-flow oxygen (baseline ordinal score of 6) was 10 days in the

combination group and 18 days in the control group (rate ratio for recovery, 1.51; 95% CI, 1.10

1 All to 2.08). Among patients with a baseline score of 4 (no oxygen) and 5 (supplemental oxygen), the rate ratio for recovery was 0.88 (95% CI, 0.63 to 1.23) and 1.17 (95% CI, 0.98 to 1.39), respectively. For those receiving mechanical ventilation or ECMO at enrollment (baseline ordinal score of 7), the rate ratio for recovery was 1.08 (95% CI, 0.59 to 1.97). The rate ratio for recovery among the 223 patients who received glucocorticoids for clinical indications during the trial was 1.06 (95% CI, 0.75 to 1.48). A sensitivity analysis with a random effect for hospital site yielded similar results (conditional random-effects estimate of rate ratio for recovery, 1.16; 95%

CI, 1.01 to 1.33; restricted maximum likelihood-based random-effects estimate of variance,

0.0305).

[0373] Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time

and accelerating improvement in clinical status, notably among patients receiving high-flow

oxygen or noninvasive mechanical ventilation. The combination was associated with fewer

serious adverse events.

[0374] All publications, patents, and patent documents cited herein above are incorporated by

reference herein, as though individually incorporated by reference.

[0375] The invention has been described with reference to various specific and preferred

embodiments and techniques. However, one skilled in the art will understand that many

variations and modifications may be made while remaining within the spirit and scope of the

invention.

[0376] Reference to any prior art in the specification is not an acknowledgement or suggestion

that this prior art forms part of the common general knowledge in any jurisdiction or that this

prior art could reasonably be expected to be combined with any other piece of prior art by a

skilled person in the art.

Claims

WHAT IS CLAIMED IS:

1. A method for treating or preventing a 2019-nCoV infection in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula I:

R8

R10

R7 N

0 N N R9

R4 R1 3 2 R R

Formula I

or a pharmaceutically acceptable salt or ester, thereof;

wherein:

each R 1 is H or halogen;

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl or (C2-Cs)substituted alkynyl;

(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, (C1-Cs)substituted alkyl, (C2-C)alkenyl,

(C2-Cs)substituted alkenyl, (C2-Cs)alkynyl, (C2-Cs)substituted alkynyl, or

(C6-C20)aryl(C1-Cs)alkyl;

R 7 is selected from a group consisting of

a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R",

-S(O) 2R",-S(O)(OR"l),-S(O) 2(OR"),or-SO 2NR"R1 2

, wherein each (C1-C)alkyl, (C2-C)alkenyl, (C2-Cs)alkynyl or

(C6-C20)aryl(Cl-C)alkyl of each R" or R 12 is, independently,

optionally substituted with one or more halo, hydroxy, CN, N3,

N(Ra) 2 or ORa; and wherein one or more of the non-terminal

carbon atoms of each said (C1-C)alkyl may be optionally

replaced with -0-, -S- or -NRa_

b)

0 0 0 O 0 HO-P- H

HO HO HO or HO O

c)

Rc 0 Rc So. 0O-P ~ Reei 0 e2d1 4, Rd N R e2 'Rd (CH 2 )n (CH 2 )n'

0 00 / O / 0 R Rf ,or R9 R9

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl,

1 A7

N N

and

Rd is H or CH 3 ;

R° and Re2 are each independently H, (Cl-C6)alkyl or benzyl;

Rf is selected from H, (C1-C8)alkyl, benzyl, (C3-C)cycloalkyl,

and -CH2-(C3-C6)cycloalkyl;

R9 is selected from (C1-C8)alkyl, -O-(C1-C8)alkyl, benzyl,

-O-benzyl, -CH2-(C3-C)cycloalkyl,

-O-CH2-(C3-C6)cycloalkyl, and CF 3 ; and

n' is selected from 1, 2, 3, and 4; and

d) a group of the formula:

Q

Z1 ,

z2

wherein:

Q is 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR 2;

Z' and Z2 , when taken together, are -Q'(C(RY)2)3Q -

wherein

each Q 1 is independently 0, S, or NR; and

each R is independently H, F, Cl, Br, I, OH, R,-C(=Q 2)R,

-C(=Q2)OR, -C(=Q2)N(R)2, -N(R)2, -+N(R)3, -SR,

-S(O)R, -S(O) 2R, -S(O)(OR), -S(O) 2(OR),

1A95

-OC(=Q')R, -OC(=Q2)OR, -OC(=Q2)(N(R)2),

-SC(=Q2)R, -SC(=Q2)OR, -SC(=Q2)(N(R)2),

-N(R)C(=Q2)R, -N(R)C(=Q2)OR,

-N(R)C(=Q 2)N(R) 2 , -SO 2 NR 2 , -CN, -N3, -N02,

-OR, or Z3; or when taken together, two R on the

same carbon atom form a carbocyclic ring of 3 to 7

carbon atoms;

each Q 2 is independently, 0, S, NR, 'N(O)(R), N(OR),

*N(O)(OR), or N-NR2;or

Z' and Z2 are each, independently, a group of the Formula Ia:

Q2

RX Q 3 p3__

Q3

M2

Formula Ia

wherein:

each Q 3 is independently a bond, 0, CR 2 , NR, 'N(O)(R),

N(OR), *N(O)(OR), N-NR 2 , S, S-S, S(O), or

S(O)2;

M2 is 0, 1 or 2;

each RX is independently R or the formula:

16A0

Q2R RQ

Q3 3 -Ry Q0 M12c ' Mld Mia M1c

wherein:

each Mla, Mlc, and Mid is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Z 3 is Z 4 or Z5;

Z4 is R,-C(Q 2 )Ry, -C(Q 2 )Z5 , -SO 2 RY, or -S0 2Z5;

and

Z 5 is a carbocycle or a heterocycle wherein Z5 is

independently substituted with 0 to 3 R

groups;

-CH(=NR"), -CH=NNHR"1, -CH=N(OR"1), -CH(OR"1)2, -C(=0)NR"R12

-C(=S)NR"R 12 , -C(=O)OR 1 1, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl,

(C 4-C8)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-C8)alkyl, -S(O).(C1-C8)alkyl,

(C6-C20)aryl(C1-C8)alkyl, OR" or SR";

NO, N02, CHO, CN, -CH(=NR"), -CH=NHNR", -CH=N(OR1 1 ), -CH(OR 1 ) 2 ,

-C(=O)NR"R 12 , -C(=S)NR"R 12 , -C(=O)OR 1 1, R1 1, OR" or SR";

(C4-C8)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C1-C)alkyl, -S(O).(C1-Cs)alkyl or

(C6-C20)aryl(Cl-C)alkyl; or R" and R 12 taken together with a nitrogen to which

they are both attached form a 3 to 7 membered heterocyclic ring wherein any one

-NR a_

each Ra is independently H, (C1-C)alkyl, (C2-C)alkenyl, (C2-C)alkynyl,

(C6-C20)aryl(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, -C(=O)R, -C(=O)OR,

wherein

heterocyclyl, (C6-C20)aryl(C1-Cs)alkyl or substituted (C-C20)aryl(C1-C)alkyl;

each n is independently 0, 1, or 2; and

of each R 2 , R 3 , R5 , R, R 1 1 or R 12 is, independently, optionally substituted with one or more halo,

hydroxy, CN, N3, N(Ra) 2 or ORa; and wherein one or more of the non-terminal carbon atoms of

each said (C1-Cs)alkyl may be optionally replaced with -0-, -S- or -NRa.

2. The method of claim 1, comprising administering to the human (i) a loading dose of the compound of Formula I and (ii) one or more of a maintenance dose of the compound of Formula I.

1'71

3. The method of claim 2, wherein the loading dose is about 150-250 mg of the compound of Formula I.

4. The method of claim 2 or 3, wherein the loading dose is about 200 mg of the compound of Formula I.

5. The method of any one of claims 2-4, wherein the maintenance dose is about 50-150 mg of the compound of Formula I.

6. The method of any one of claims 2-5, wherein the maintenance dose is about 100 mg of the compound of Formula I.

7. The method of any one of claims 2-6, comprising administering one loading dose of about 150-250 mg and at least one maintenance dose of about 50-150 mg.

8. The method of any one of claims 2-7, comprising administering one loading dose of 150 250 mg on treatment day one and the maintenance dose of about 50-150 mg on each of the following day.

9. The method of any one of claims 2-8, comprising administering one loading dose of 150 250 mg on treatment day one and the maintenance dose of about 50-150 mg on day 2 to day 10 of the treatment.

10. The method of any one of claims 2-9, comprising administering one loading dose of 150 250 mg on treatment day one and the maintenance dose of about 50-150 mg on day 2 to day 5 of the treatment.

11. The method of any one of claims 1-10, wherein the compound of Formula I is administered by intramuscular administration.

12. The method of any one of claims 1-10, wherein the compound of Formula I is administered by inhalation, IV infusion, orally or subcutaneously.

13. The method of any one of claims 1-10 and 12, wherein the compound of Formula I is administered by inhalation or IV infusion.

14. The method of any one of claims 1-10, 12, and 13, wherein the compound of Formula I is administered by inhalation.

1'7)

15. The method of any one of claims 1-10, 12, and 13, wherein the compound of Formula I is administered by IV infusion.

16. The method of any one of claims 1-13, wherein at least one dose of the compound of Formula I is administered by inhalation and at least one dose of the compound of Formula I is administered by IV infusion.

17. The method of any one of claims 1-16, wherein the 2019-nCoV infection is caused by type L SARS-CoV-2.

18. The method of any one of claims 1-16, wherein the 2019-nCoV infection is caused by type S SARS-CoV-2.

19. The method of any one of claims 1-18, wherein the 2019-nCoV infection is caused by UK SARS-CoV-2 variant B.1.1.7.

20. The method of any one of claims 1-18, wherein the 2019-nCoV infection is caused by South Africa SARS-CoV-2 501.V2.

21. The method of any one of claims 1-20, wherein the 2019-nCoV infection is caused by a virus having at least 85% sequence homology to the whole genome of SARS-CoV-2.

22. The method of any one of claims 1-20, wherein the 2019-nCoV infection is caused by a virus having at least 90% sequence homology to the whole genome of SARS-CoV-2.

23. The method of any one of claims 1-20, wherein the 2019-nCoV infection is caused by a virus having at least 95% sequence homology to the whole genome of SARS-CoV-2.

24. The method of any one of claims 1 or 23, wherein the 2019-nCoV infection is caused by a virus having at least 97% sequence homology to the whole genome of SARS-CoV-2.

25. The method of any one of claims 1-24, wherein the 2019-nCoV infection is caused by a virus having at least 99% sequence homology to the whole genome of SARS-CoV-2.

1 '7

26. The method of any one of claims 1-25, wherein the 2019-nCoV infection is caused by a virus having at least 85% sequence homology to the SARS polymerase.

27. The method of any one of claims 1-26, wherein the 2019-nCoV infection is caused by a virus having at least 90% sequence homology to the SARS polymerase.

28. The method of any one of claims 1-27, wherein the 2019-nCoV infection is caused by a virus having at least 95% sequence homology to the SARS polymerase.

29. The method of any one of claims 1-28, wherein the 2019-nCoV infection is caused by a virus having at least 97% sequence homology to the SARS polymerase.

30. The method of any one of claims 1-29, wherein the 2019-nCoV infection is caused by a virus having at least 99% sequence homology to the SARS polymerase.

31. The method of any one of claims 1-30, wherein

the compound is a compound of Formula IV:

NH 2

R7 N

N N

N

OH OH

Formula IV

or a pharmaceutically acceptable salt or ester, thereof;

wherein:

R 7 is selected from the group consisting of

a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R",

S(O) 2 R", -S(O)(OR"l), -S(O) 2 (OR"), or -S 2 NR"R12 ,

1'7A wherein each R 1 1 or R 12 is independently H, (C1-C)alkyl, (C2-C)alkenyl, (C 2

Cs)alkynyl, (C4-Cs)carbocyclylalkyl, optionally substituted aryl,

optionally substituted heteroaryl, -C(=O)(C-C)alkyl, -S(O).(C 1

Cs)alkyl or aryl(C1-Cs)alkyl; or R" and R 12 taken together with a

nitrogen to which they are both attached form a 3 to 7 membered

heterocyclic ring wherein any one carbon atom of said

heterocyclic ring can optionally be replaced with -0-, -S- or -NRa;

each Ra is independently H, (C1-C)alkyl, (C2-C)alkenyl, (C2-C)alkynyl,

aryl(C1-Cs)alkyl, (C4-Cs)carbocyclylalkyl, -C(=O)R, -C(=O)OR,

C(=0)NR2, -C(=0)SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR),

or -SO 2 NR 2 ;

wherein each R is independently H, (C-Cs) alkyl, (C-Cs) substituted

alkyl, (C2-Cs)alkenyl, (C 2 -Cs) substituted alkenyl, (C 2 -Cs) alkynyl,

(C 2 -Cs) substituted alkynyl, C6-C20 aryl, C6-C20 substituted aryl,

C2-C20 heterocyclyl, C2-C20 substituted heterocyclyl, arylalkyl or

substituted arylalkyl; and

wherein each (C1-Cs)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl or aryl(C1

Cs)alkyl of each R" or R 12 is, independently, optionally

substituted with one or more halo, hydroxy, CN, N3, N(Ra) 2 or

ORa; and wherein one or more of the non-terminal carbon atoms

of each said (C1-Cs)alkyl may be optionally replaced with -0-, -S

or -NRa_

b)

1'7S

0 0 HO-P-- HO HP HO O /O HOP P HO O HO HO HO or HO HO

c)

Rc 0 Rc So. 0O-P ~ - C

R Rd e2 'Rd (CH 2 )n (CH2 )n

/ / 0 R, Rf or R9 R9

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl

N

and

Rd is H or CH 3;

R° and Re2 are each independently H, C1-C6 alkyl or benzyl;

Rf is selected from H, C-C8 alkyl, benzyl, C3-C6 cycloalkyl, and

CH 2-C 3-C 6 cycloalkyl;

R9 is selected from Ci-C8 alkyl, -o-c-C8 alkyl, benzyl, -0

benzyl, -CH 2-C 3-C 6 cycloalkyl, -O-CH2 -C 3 -C6 cycloalkyl,

and CF3 ; and

n' is selected from 1, 2, 3, and 4; and

d) a group of the formula:

17A

Q

Z1 z2

wherein

Q is 0, S, NR, 'N(O)(R), N(OR), 'N(O)(OR), or N-NR 2;

Z and Z2 , when taken together, are -Q (C(RY)2)3Q -

wherein

each Q 1 is independently 0, S, or NR; and

each R is independently H, F, Cl, Br, I, OH, R,-C(=Q 2)R,

C(=Q 2)OR, -C(=Q 2)N(R) 2 , -N(R) 2 , -+N(R) 3 , -SR, -S(O)R,

S(O) 2 R, -S(O)(OR), -S(O) 2 (OR), -OC(=Q 2)R,

OC(=Q 2 )OR, -OC(=Q 2)(N(R) 2), -SC(=Q 2)R, -SC(=Q 2)OR,

-SC(=Q 2 )(N(R) 2), -N(R)C(=Q 2 )R, -N(R)C(=Q 2 )OR,

N(R)C(=Q 2 )N(R) 2 , -SO2 NR2 , -CN, -N3, -N02, -OR, or

z3; or when taken together, two R on the same carbon

atom form a carbocyclic ring of 3 to 7 carbon atoms;

each Q 2 is independently, 0, S, NR, 'N(O)(R), N(OR),

*N(O)(OR), or N-NR2;or

Z and Z2 are each, independently, a group of the Formula Ia:

1'7'7

Q2

RX Q3 _ 3 _

Q3

M2

Formula Ia

wherein:

each Q 3 is independently a bond, 0, CR 2 , NR, 'N(O)(R), N(OR),

*N(O)(OR), N-NR 2, S, S-S, S(O), or S(O)2;

M2 is 0, 1 or 2;

each RX is independently R or the formula:

Q2 RY RY Q2 R~ RY Q'3 . .3Q 3 -- Ry

. 3'- M12c 'Jc Mia M1c Mid

wherein:

each Mla, Mlc, and Mid is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

Z 3 is Z 4 or Z5 ;

Z4 is R, -C(Q 2 )Ry, -C(Q 2)Z5 , -SO2RY, or -SO2Z5; and

Z 5 is a carbocycle or a heterocycle wherein Z5 is independently substituted with 0 to 3 R

groups.

32. The method of any one of claims 1-31, wherein Z 4 is R, -C(Q 2)Z 5, or -S0 2Z;

Z 5 is a carbocycle or a heterocycle;

each R 1 1 or R 12 is independently H, (C1-C)alkyl, (C2-C)alkenyl,

(C2-Cs)alkynyl, (C4-Cs)carbocyclylalkyl, (C6-C20)optionally substituted aryl, optionally

substituted heteroaryl, -C(=O)(C1-Cs)alkyl, -S(O)n(C1-Cs)alkyl or

(C6-C20)aryl(C1-C)alkyl; or R" and R 12 taken together with a nitrogen to which they

are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom

of said heterocyclic ring can optionally be replaced with -0-, -S- or -NH-; and wherein

hydroxy, CN, N3, NH2 or OH; and wherein one or more of the non-terminal carbon atoms of

each said (C1-Cs)alkyl may be optionally replaced with -0-, -S- or -NH-.

33. The method of any one of claims 1-32, wherein R 7 is H.

34. The method of any one of claims 1-32, wherein R 7 is selected from the group of

a) H, -C(=O)R", -C(=O)OR", -C(=O)NR"R 12 , -C(=O)SR", -S(O)R", -S(O) 2 R",

S(O)(OR 1 ), -S(O) 2 (OR"), -S 2 NR"R1 2

b)

0 0 0 O 0 P'0 HO-P- H | HP /P 0 HO O HO HO HO or HO HO HO

and

1'70 c)

Rc 0 Rc S el0-P el __

N O 2 R ReRRd e2 sRd (CH 2 ), (CH2 )n

0 / O R, Rf or Rg Rg

wherein:

R' is selected from phenyl, 1-naphthyl, 2-naphthyl,

N

and

Rd is H or CH 3;

R° and Re2 are each independently H or C1-C6 alkyl;

Rf is selected from H, C-C8 alkyl, benzyl, C3-C6 cycloalkyl, and

CH 2-C 3-C 6 cycloalkyl;

Rg is selected from C1-C8 alkyl, -0-C1-C8 alkyl, benzyl, -0

benzyl, -CH 2-C 3-C 6 cycloalkyl, -O-CH2 -C 3 -C6 cycloalkyl,

and CF3 ; and

n' is selected from 1, 2, 3, and 4.

35. The method of any one of claims 1-32, wherein R 7 is

0

1 RA wherein Z' and Z 2 are each, independently, a group having the structure:

R3 RY

M12c

and Z 3 is Z5 .

36. The method of any of claims 1-32, 34 or 35, wherein R 7 is

00 0 0 0o HO-P

HO , HO H O O HO , or

0

Zi z2

wherein Z' and Z 2 are each, independently, a group having the structure:

RQ RY

M12c

and Z 3 is Z5 .

37. The method of any one of claims 1-32, wherein R 7 is

0 Rx

Q3b

RX

wherein each Q3b is, independently, 0 or N(R).

19R1

38. The method of claim 37, wherein each Q3b is 0 and each RXis independently:

R R 0

Q3 Q3 R M12c

wherein M12c is 1, 2 or 3 and each Q 3 is independently a bond, 0, CR 2, or S.

39. The method of any of claims 1-32 or 34-37, wherein R 7 is

(RY) 0-3

0 O CH 3 OR H 0

40. The method of any of claims 1-32, 34 or 36, wherein R 7 is

00 0 0 0 0 HO--- - HO /I HO O HO HO HO HO HO HO

0 R S / 0

R 0 or

S15I

41. The method of any of claims 1-32 or 34 wherein R 7 is

0O CH 3 \ O CH 3

N OR OR'

0 or 0

wherein

Rf is selected from the group of from H, C-C8 alkyl, benzyl, C3-C cycloalkyl, and -CH 2-C 3-C6

cycloalkyl.

42. The method of claim 41, wherein Rf is C1-C8 alkyl.

43. The method of any of claims 1-32 or 34, wherein R 7 is

HO-P # ~ HO--P # P, ,P #

HO , HO OHO / 0P HOO - HO HO H

0

I IL

or R NH R NH R9 O

wherein

Rf is selected from H, C-C8 alkyl, benzyl, C3-C cycloalkyl, and -CH 2 -C 3 -C6 cycloalkyl; and

R9 is selected from C-C8 alkyl, -0-C1-C8 alkyl, benzyl, -O-benzyl,-CH2 -C 3 -C6 cycloalkyl, -0

CH 2 -C 3 -C 6 cycloalkyl, and CF 3 .

44. The method of any of claims 1-32, 34 or 43, wherein R 7 is

0 O- - O-P RO NH orRNH or

wherein

Rf is selected from H, C1-C8 alkyl, benzyl, C3-C cycloalkyl, and -CH 2 -C 3 -C cycloalkyl.

45. The method of claim 44, wherein Rf is C1-C8 alkyl.

46. The method of claim 44, wherein Rf is C1-C6 alkyl.

47. The method of any one of claims 1-32, 34 or 43, wherein R 7 is:

0 R9 0 O

wherein

CH 2 -C 3 -C 6 cycloalkyl, and CF 3 .

48. The method of claim 47, wherein R9 is C-C8 alkyl.

49. The method of any of claims 1-32, 34, 36, 40 or 43, wherein R 7 is selected from the group of:

00 0 0 0 0

HO-P-i- HO-P __ and O and / O HO HO HO , HO HO

50. The method of any of claims 1, 34, 36, 40 or 43, wherein R 7 is

0 H 0P 0P 0 0 04 HO-P- 0 / / 0/ - HO O HO HO H HO HO HO

0O0 S '* O-P-Q 10

00 0 0 O NH ONH

YY O-P -P-P'

O NH N NH or

51. The method of any one of claims 1-32, wherein the compound of Formula IV is:

NH 2 NH 2

N NH N N N N, N

HOO'CNH OOH. H HHO OH

HHO\0 ONPJ 0 OC NHNH NN NH2 2

H H OH OH

15&SNH

NH 2

N

NN 0 HN-P-O

HO O \NH2N NH 2 NH 2 S N O-P 11 \ NJ 090 O O N s- CHO'OOO 0 N

Hd 'ONH O , or Hd OH

or a pharmaceutically acceptable salt or ester thereof.

52. The method of any one of claims 1-32, wherein the compound of Formula IV is:

NH 2 NH 2 N N -- --

oo-P-o 0 O-P-O O NH oHO H oH OH N NH HO OH N

NH 2 0N NH 2 11 O N, N N H 1 ' CN -P- 0 N,

O NH H OH

NH2 NH 2

O -" N O N PhO-P-O O N NN 0-0- NN HN( ' ,, NH

0O 0 OH 00 HO OH

NH 2 NH 2 N 0 N O N, ) O N,I qO-P--O -,N 0-P-- , N oO 'CN 0 'CN O NH HO OH O NH HO OH

o NH 2 NH 2 H to H 0 N / N 0 N 0

O O N OHO N NH

Hd OH H OH

" oO b HN 0 NH N0 b Hd OH N O' O NNO O N~

N N

NH 2

OH CNN

or ;

or apharmaceutically acceptable salt or ester thereof. NN N

53. The method of any one of claims 1-32, wherein the compound of Formula IV is: 'C ,C Hd oHV NH 2

NH 2 N

NS O -O ON N~

HO 0- HONOH

HN 0 :H

12'7

NH 2 NH 2

\NN 0 \N, 101 0 0 N O-P-O NH 00-P-0

O O H0 HO OH

NH 2

NH 2 0 N 11C N OOPO NN~ 0 -P- HOGH

NH NHH o

I'O NH OH od OH

NH 2 NH 2

o-- " N0 0-P--O N N, OH: INH HO ~ H5 HO 'N 000

NH 2 oNH 2

0N 0 H

0 N O HQ 'N' OH 00HC

1 Hb b Olj', 0 : H6 o NH 2 0 NH 2

O N N O- ON0 N,

NN HG OH I HG OH

0 0 N~O NH 2 NNH 2

N N

OH- N N 0--O

1b Hd H 0 H H

0 NJ 90 0 N 0 N"-0N, NH 2 0 H"P0 NH2 * N 0 NN

HO 0 HO N

H0 OH orHd oH

or apharmaceutically acceptable salt or ester thereof.

54. The method of claim 1-32, 51, and 53, wherein the compound of Formula IV is:

NH 2 SN N

oN 0 z S. N HO "O'N

HO OH , or apharmaceutically acceptable salt or ester thereof.

55. The method claim 1-32, or aofpharmaceutical and 53,saltoetrhrof cceptabe wherein the compound of Formula IV is:

NH 2 NH 2

0 HN-P 0 HN"P-O H5 OH 0rHO OH

or1 or a pharmaceutically acceptable salt or ester thereof.

56. The method of any of claims 1-55, wherein the compound of Formula IV is:

NH 2

N

O N'N o HN-P-O HO OH

or a pharmaceutically acceptable salt or ester thereof.

57. The method of any one of claims 1-56, wherein the human is suffering from the COVID 19 disease caused by the 2019-nCoV (SARS-CoV-2).

58. The method of any one of claims 1-57, wherein the method comprises event driven administration of the compound of Formula I,II, III, or IV, or a pharmaceutically acceptable salt thereof, to the subject.

59. The method of claim 58, wherein the event driven administration comprises pre exposure prophylaxis (PrEP).

60. The method of claim 58, wherein the event driven administration comprises post exposure prophylaxis (PEP).

61. The method of claim 58, wherein the event driven administration comprises pre exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP).

62. The method of any one of claims 1-61, wherein the method comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof.

63. The method of any of claims 1-62, further comprising administering a pharmaceutically acceptable carrier or excipient.

64. The method of any of claims 1-63, further comprising administering a therapeutically effective amount of an additional therapeutic agent.

10QA

65. The method of claim 64, wherein the additional therapeutic agent is an anti-inflammatory agent.

66. The method of claim 64 or 65, wherein the additional therapeutic agent is selected from the group consisting of baricitinib, tocilizumab, cenicriviroc, icatibant, apremilast, razuprotafib, lenzilumab, risankizumab, infliximab, and abatacept.

67. The method of claim 64-65, wherein the additional therapeutic agent is baricitinib.

68. The method of claim 64, wherein the additional therapeutic agent is a JAK inhibitor.

69. The method of claim 64 or 68, wherein the additional therapeutic agent is barcitinib, ruxolitinib, tofacitinib, upadacitinib, or fedratinib.

70. The method of claim 64, 68, or 69 wherein the additional therapeutic agent is barcitinib.

71. The method of claim 64, wherein the additional therapeutic agent is an antibody.

72. The method of claim 64 or 71, wherein the additional therapeutic agent is anti-S neutralizing antibody.

73. The method of claim 64, wherein the additional therapeutic agent is corticosteroid.

74. The method of claim 64, wherein the additional therapeutic agent is dexamethasone.

75. The method of claim 64, wherein the additional therapeutic agent is an antiviral agent.

76. The method of claim 64 or 75, wherein the additional therapeutic agent is an antiviral agent selected from the group consisting of 5-substituted 2'-deoxyuridine analogues, nucleoside analogues, pyrophosphate analogues, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, entry inhibitors, acyclic guanosine analogues, acyclic nucleoside phosphonate analogues, HCV NS5A or NS5B inhibitors, influenza virus inhibitors, interferons, immunostimulators, oligonucleotides, antimitotic inhibitors, and combinations thereof.

77. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is a 5 substituted 2'-deoxyuridine analogue.

78. The method of any one of claims 64 and 75-77, wherein the additional therapeutic agent is idoxuridine, trifluridine, or brivudine [BVDU].

79. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is a nucleoside analogue.

80. The method of claim 64, 75, 76, or 79, wherein the additional therapeutic agent is selected from the group consisting of favipiravir, ribavirin, galidesivir, and combinations thereof.

81. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is a pyrophosphate analogue.

82. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is nucleoside reverse transcriptase inhibitor.

83. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is a non nucleoside reverse transcriptase inhibitor.

84. The method of claim 64 or 76, wherein the additional therapeutic agent is a protease inhibitor.

85. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an integrase inhibitor.

86. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an entry inhibitor.

87. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an acyclic guanosine analogue.

88. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an acyclic nucleoside phosphonate analogue.

89. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is a HCV NS5A or NS5B inhibitor.

90. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an influenza virus inhibitor.

102)

91. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an interferon.

92. The method of claim 91, wherein the additional therapeutic agent is interferon beta-ia.

93. The method of claim 91, wherein the additional therapeutic agent is interferon alfacon 1, interferon alfa lb, interferon alfa 2a, interferon alfa 2b, or a combination thereof.

94. The method of claim 91, wherein the additional therapeutic agent is pegylated interferon alfa-2a, pegylated interferon alfa-2b, or a combination thereof.

95. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an immunostimulatory agent.

96. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an oligonucleotide.

97. The method of claim 64, 75, or 76, wherein the additional therapeutic agent is an antimitotic inhibitor.

98. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of RSV.

99. The method of any one of claims 75-97 and 98, wherein the antiviral agent is ALS-8112 or presatovir.

100. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of picornavirus.

101. The method of any one of claims 75-97 and 100, wherein the antiviral agent is a picornavirus polymerase inhibitor.

102. The method of any one of claims 75-97, 100, and 101, wherein the antiviral agent is rupintrivir.

103. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of influenza.

104. The method of any one of claims 75-97 and 103, wherein the antiviral agent is selected

1Qq from the group consisting of arbidol (umifenovir), baloxavir marboxil, oseltamivir, peramivir, ingavirin, laninamivir octanoate, zanamivir, favipiravir, rimantadine, favipiravir, and combinations thereof.

105. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of malaria.

106. The method of any one of claims 75-97 and 105, wherein the antiviral agent is selected from the group consisting of hydroxychloroquine, chloroquine, artemether, lumefantrine, atovaquone, proguanil, tafenoquine, pyronaridine, artesunate, artenimol, piperaquine, artesunate, amodiaquine, pyronaridine, artesunate, halofantrine, quinine sulfate, mefloquine, solithromycin, pyrimethamine, MMV-390048, ferroquine, artefenomel mesylate, ganaplacide, DSM-265, cipargamin, artemisone, and combinations thereof.

107. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of coronavirus.

108. The method of any one of claims 75-97 and 107, wherein the antiviral agent is selected from a group consisting of IFX-1, FM-201, CYNK-001, DPP4-Fc, ranpirnase, nafamostat, LB-2, AM-1, anti-viroporins, and combinations thereof.

109. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of ebola virus.

110. The method of any one of claims 75-97 and 109, wherein the antiviral agent is selected from a group consisting of ribavirin, palivizumab, motavizumab, RSV-IGIV (RespiGam©), MEDI-557, A-60444, MDT-637, BMS-433771, amiodarone, dronedarone, verapamil, Ebola Convalescent Plasma (ECP), TKM-100201, BCX4430 ((2S,3S,4R,5R) 2-(4-amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol), favipiravir (also known as T-705 or Avigan),T-705 monophosphate, T-705 diphosphate, T-705 triphosphate, FGI-106 (1-N,7-N-bis[3-(dimethylamino)propyl]-3,9 dimethylquinolino[8,7-h]quinolone-1,7-diamine), JK-05, TKM-Ebola, ZMapp, rNAPc2, VRC-EBOADC076-00-VP, OS-2966, MVA-BN filo, brincidofovir, Vaxart adenovirus vector 5-based ebola vaccine, Ad26-ZEBOV, FiloVax vaccine, GOVX-E301, GOVX E302, ebola virus entry inhibitors (NPC1 inhibitors), or rVSV-EBOV or mixtures

10A1 thereof.

111. The method of claim 109 or 110, wherein the antiviral agent is ZMapp, mAB114, REGEN-EB3, and combinations thereof.

112. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of HCV.

113. The method of any one of claims 75-97 and 112, wherein the antiviral agent is a HCV polymerase inhibitor.

114. The method of claim 113, wherein the HCV polymerase inhibitor is selected from the group consisting of sofosbuvir, GS-6620, PSI-938 , ribavirin, tegobuvir, radalbuvir, MK 0608, and combinations thereof.

115. The method of any one of claims 75-97 and 112, wherein the antiviral agent is a HCV protease inhibitor.

116. The method of claim 115, wherein the HCV protease inhibitor is selected from the group consisting of GS-9256, vedroprevir, voxilaprevir, and combinations thereof.

117. The method of any one of claims 75-97, wherein the antiviral agent is a NS5A inhibitor.

118. The method of claim 117, wherein the NS5A inhibitor is selected from the group consisting of ledipasvir, velpatasvir, and combinations thereof.

119. The method of any one of claims 75-97 and 112, wherein the additional therapeutic agent is selected from the group consisting of daclatasvir, ledipasvir, ombitasvir, elbasvir, sofosbuvir, dasabuvir, ribavirin, asunaprevir, simeprevir, paritaprevir, ritonavir, elbasvir, grazoprevir, and combinations thereof.

120. The method of any one of claims 75-97, wherein the antiviral agent is an anti HBV agent.

121. The method of claim 120, wherein the antiviral agent is a HBV polymerase inhibitor.

122. The method of claim 120, wherein the antiviral agent is a HBV capsid inhibitor.

123. The method of any one of claims 75-97, wherein the antiviral agent is an agent for treatment of HIV.

124. The method of claim 123, wherein the antiviral agent is selected from the group consisting of HIV protease inhibitors, HIV integrase inhibitors, entry inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nonnucleoside reverse transcriptase inhibitors, acyclic nucleoside phosphonate analogues, and combinations thereof.

125. The method of claim 123 or 124, wherein the antiviral agent is a HIV protease inhibitor.

126. The method of claim 125, wherein the HIV protease inhibitor is selected from the group consisting of darunavir, cobicistat, ASC-09, atazanavir, lopinavir, ritonavir, tipranavir, nelfinavir, fosamprenavir, amprenavir, saquinavir, indinavir, AEBL-2, MK-8718, GS 9500, atazanavir, tipranavir, GS-1156, and combinations thereof.

127. The method of claim 125, wherein the HIV protease inhibitor is selected from the group consisting of saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, darunavir, tipranavir, and combinations thereof.

128. The method of claim 123 or 124, wherein the antiviral agent is a HIV integrase inhibitor.

129. The method of claim 128, wherein the HIV integrase inhibitor is selected from the group consisting of raltegravir, elvitegravir, dolutegravir, cabotegravir, bictegravir, MK-8591 and combinations thereof.

130. The method of claim 123 or 124, wherein the antiviral agent is an HIV entry inhibitor.

131. The method of claim 130, wherein the antiviral agent is leronlimab.

132. The method of claim 123 or 124, wherein the antiviral agent is a HIV nucleoside reverse transcriptase inhibitor.

133. The method of claim 132, wherein the HIV nucleoside reverse transcriptase inhibitor is selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, emtricitabine, and combinations thereof.

134. The method of claim 123 or 124, wherein the antiviral agent is a HIV nonnucleoside reverse transcriptase inhibitors.

135. The method of claim 134, wherein the HIV nonnucleoside reverse transcriptase inhibitor is selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and combinations thereof.

136. The method of claim 123 or 124, wherein the antiviral agent is an acyclic nucleoside phosphonate analogue.

137. The method of claim 123, wherein the antiviral agent is a HIV capsid inhibitor.

138. The method of claim 64, wherein the additional therapeutic agent is selected from the group consisting of colistin, valrubicin, icatibant, bepotastine, epirubicin, epoprosetnol, vapreotide, aprepitant, caspofungin, perphenazine, atazanavir, efavirenz, ritonavir, acyclovir, ganciclovir, penciclovir, prulifloxacin, bictegravir, nelfinavir, tegobuvi, nelfinavir, praziquantel, pitavastatin, perampanel, eszopiclone, and zopiclone.

139. The method of claim 64 or 75, wherein the additional therapeutic agent is a proteasome inhibitor.

140. In method of claim 139, wherein the additional therapeutic agent is selected from the group consisting of ixazomib, carfilzomib, marizomib, bortezomib, and combinations thereof.

141. The method of claim 64, wherein the additional therapeutic agent is a BTK inhibitor.

142. The method of claim 64 or 141, wherein the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, acalabrutinib, and combinations thereof.

143. The method of claim 64 or 141, wherein the additional therapeutic agent is selected from a group consisting of tirabrutinib, ibrutinib, and combinations thereof.

144. The method of claim 64, wherein the additional therapeutic agent is a KRAS inhibitor.

145. The method of claim 64, wherein the additional therapeutic agent is a vaccine.

146. The method of claim 64 or 145, wherein the additional therapeutic agent is a DNA vaccine, RNA vaccine, live-attenuated vaccine, protein based vaccine, or a combination thereof.

147. The method of claim 64 or 145, wherein the additional therapeutic agent is a 2019

1 '7 nCoV.

148. The method of claim 64 or 145, wherein the additional therapeutic agent is INO-4800 or INO-4700

149. The method of claim 64, wherein the additional therapeutic agent is an antibody.

150. The method of claim 64 or 149, wherein the additional therapeutic agent is a 2019-nCoV antibody.

151. The method of claim 64, wherein the additional therapeutic agent is recombinant cytokine gene-derived protein injection.

152. The method of claim 64, wherein the additional therapeutic agent is a polymerase inhibitor.

153. The method of claim 152, wherein the additional therapeutic agent is a DNA polymerase inhibitor.

154. The method of claim 153, wherein the DNA polymerase inhibitor is cidofovir.

155. The method of claim 152, wherein the additional therapeutic agent is a RNA polymerase inhibitor.

156. The method of claim 155, wherein the RNA polymerase inhibitor is selected from the group consisting of ribavirin, favipiravir, lamivudine, pimodivir and combination thereof.

157. The method of claim 155 or 156, wherein the RNA polymerase inhibitor is selected from the group consisting of ribavirin, favipiravir, pimodivir and combination thereof.

158. The method of claim 64 or 75, wherein the additional therapeutic agent is selected from the group consisting of lopinavir, ritonavir, interferon-alpha-2b, ritonavir, arbidol, hydroxychloroquine, darunavir and cobicistat, abidol hydrochloride, oseltamivir, litonavir, emtricitabine, tenofovir alafenamide fumarate, baloxavir marboxil, ruxolitinib, and combinations thereof.

159. The method of claim 64, wherein the additional therapeutic agent is methylprednisolone.

160. The method of claim 64, wherein the additional therapeutic agent is an immunomodulator.

161. The method of any of claims 1-63, further comprising administering a therapeutically effective amount of at least one other therapeutic agent or composition thereof selected from the group consisting of a corticosteroid, an anti-inflammatory signal transduction modulator, a 2-adrenoreceptor agonist bronchodilator, an anticholinergic, a mucolytic agent, hypertonic saline and other drugs for treating a 2019-nCoV infection; or mixtures thereof.

162. The method of any of claims 1-63, wherein a 2019-nCoV polymerase is inhibited.

163. A compound as described in any of claims 1-63, or a pharmaceutically acceptable salt or ester thereof, for use in treating a 2019-nCoV virus infection in a human.

164. The use of a compound as described in any of claims 1-63, or a pharmaceutically acceptable salt or ester thereof, for use in the preparation of a medicament useful in treating a 2019-nCoV virus infection in a human.

165. A kit comprising one or more individual dosage units of a compound selected from those described in claims 1-63, or a pharmaceutically acceptable salt, ester, stereoisomer, hydrate, solvate, mixture of stereoisomers, or tautomer thereof, and directions for their use in treating a 2019-nCoV viral infection in a human.

166. The kit of claim 165, further comprising the additional therapeutic agent of any one of claims 64-165.